{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Nuclear Lamina as Global Regulator", "entry_form": "claim", "gradeable_restatement": "The nuclear lamina globally regulates gene expression by tethering and silencing lamina-associated domains, rather than serving a primarily mechanical role.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, developmental window, exposure, baseline disease and measurement fixed before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Nuclear Lamina as Global Regulator", "central_claim": "The nuclear lamina globally regulates gene expression by tethering and silencing lamina-associated domains, rather than serving a primarily mechanical role.", "proposed_mechanism": "The nuclear lamina globally regulates gene expression by tethering and silencing lamina-associated domains, rather than serving a primarily mechanical role.", "claimed_scope": "Global lamina-mediated transcriptional repression across predefined cell states, distinguished from contextual topology, envelope-tether redundancy and mechanical signaling", "claimed_level": [ "initiation", "maintenance", "progression" ], "is_conjunctive": true, "conjunctive_note": "Index scope-matched retained. The registered headline is global across cell states: SC4 is the full-scope comparison; narrow topological SC2 success is reported separately rather than replacing the global claim." }, "rubric_routing": { "primary_rubric": "03-epigenetics-gene-regulation.md", "secondary_rubrics": [], "index_notes_applied": [ "Index scope-matched retained. The registered headline is global across cell states: SC4 is the full-scope comparison; narrow topological SC2 success is reported separately rather than replacing the global claim." ], "rubric_fit_note": "03-epigenetics-gene-regulation directly covers lamina-associated control. Native intact-cell endogenous loci/proteins with functional transcription and cell-state controls are assessed as field-valid cellular systems under its endogenous perturbation definitions; purified biochemistry, synthetic reporter behavior and polymer simulation are not elevated to native causal proof. Mechanical/survival/replication effects of whole lamin loss must be separated from direct silencer recruitment. The registered global SC4 gate is retained and narrow SC2 does not replace it." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "LAD genes are less transcriptionally active.", "subclaim_type": "existence", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "LAD genes have lower average expression across organism and cell-state maps, with active escapers and dynamic intermediate peripheral domains. This descriptive existence claim remains Β; lamina contact does not itself identify a causal silencer." }, { "id": "SC2", "statement": "Lamins causally maintain topology and speckle distance with transcriptional effects in defined contexts.", "subclaim_type": "mechanism", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Endogenous lamin loss/restoration changes topology and functional gene regulation in defined contexts. Matched cell-cycle TKO/B1-rescue experiments, specific Drosophila loci, heat-shock responses and Gata4-dependent lineage rescue support a genuine contribution, with stem-state, isoform and mechanical boundaries. Whole-protein loss does not isolate every topology/speckle mediator." }, { "id": "SC3", "statement": "Lamina recruitment of enzymatic silencers is necessary for LAD repression.", "subclaim_type": "mechanism", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Local HDAC/SIRT7 and lamin-dependent effects provide mechanistic support, but enzyme activity required for repression is not the same as necessity of recruitment by lamin. HDAC1 silencing can change without detachment, HDAC3 detachment can change without silencing, and native/reporter screens implicate chromatin regulators with weak/variable NL dependence. Selective recruitment-defective loss/rescue at native LADs remains unverified." }, { "id": "SC4", "statement": "Lamina tethering and silencing globally regulates transcription across cell states.", "subclaim_type": "generalization", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The global direct-tethering/silencing claim is not supported by lamina association alone and is challenged by lamin-null stem-cell competence, lack of preferential LAD derepression, transcriptionally competent peripheral loci and short-term detachment with minor expression effects. Contextual gene regulation is real; constitutive all-state enzymatic repression rather than mechanics/network effects has not been isolated." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Index scope-matched retained. The registered headline is global across cell states: SC4 is the full-scope comparison; narrow topological SC2 success is reported separately rather than replacing the global claim.", "primary_subclaim_id": "SC4", "aggregation_derivation": "Scope-matched aggregation is fixed to global SC4 and yields Γ. SC2 has mapped context-specific Ε support, while SC1 remains Β and direct enzyme-recruitment necessity SC3 remains Γ. Whole-lamin deletion can change thousands of genes yet still fail to establish direct global repression: changes can be bidirectional, follow mechanics/stress, or depend on other envelope tethers. This is not a judgment that lamins lack regulatory function.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Spatial partitioning and speckle-distance regulation", "core_claim": "Lamina-related topology constrains access to activating compartments and supports context-dependent transcription.", "explains_what_nominal_does_not": "Lamina-related topology constrains access to activating compartments and supports context-dependent transcription.", "strongest_supporting_evidence": [ "TKO/B1 topology rescue, heat-shock myosin/speckle effects and stem-lineage rescue support architecture-linked regulation." ], "strongest_contradictory_evidence": [ "Precise speckle-distance mediation is not universally isolated; whole-lamin loss changes many functions and can reduce global transcription." ], "hsef_level_for_this_model": "Ε", "rationale": "TKO/B1 topology rescue, heat-shock myosin/speckle effects and stem-lineage rescue support architecture-linked regulation. Precise speckle-distance mediation is not universally isolated; whole-lamin loss changes many functions and can reduce global transcription." }, { "rank_in_tournament": 2, "model_id": "M4", "is_nominal": false, "name": "Redundant inner-membrane tether network", "core_claim": "LBR, LAP2, PRR14 and LEM proteins provide cell-specific anchoring with lamin cooperation rather than one indispensable filament mechanism.", "explains_what_nominal_does_not": "LBR, LAP2, PRR14 and LEM proteins provide cell-specific anchoring with lamin cooperation rather than one indispensable filament mechanism.", "strongest_supporting_evidence": [ "Sequential LBR/A-type tethers, LBR/LAP2 double-loss/rescue and NET/LEM perturbations define redundancy and lineage effects." ], "strongest_contradictory_evidence": [ "Stable anchoring loss may change marks and transcription secondarily; redundancy alone does not prove every gene effect comes from positioning." ], "hsef_level_for_this_model": "Ε", "rationale": "Sequential LBR/A-type tethers, LBR/LAP2 double-loss/rescue and NET/LEM perturbations define redundancy and lineage effects. Stable anchoring loss may change marks and transcription secondarily; redundancy alone does not prove every gene effect comes from positioning." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "Mechanotransduction and stress signaling", "core_claim": "Nuclear/cytoskeletal mechanics and damage responses cause a subset of transcription changes after lamin loss.", "explains_what_nominal_does_not": "Nuclear/cytoskeletal mechanics and damage responses cause a subset of transcription changes after lamin loss.", "strongest_supporting_evidence": [ "Strain, actin-MKL1 rescue, adult cardiac stress and human myotube load responses establish functional mechanosignaling contexts." ], "strongest_contradictory_evidence": [ "Not all mechanoregulation requires laminA/C, and native topology/lineage results cannot be reduced entirely to terminal mechanical failure." ], "hsef_level_for_this_model": "Ε", "rationale": "Strain, actin-MKL1 rescue, adult cardiac stress and human myotube load responses establish functional mechanosignaling contexts. Not all mechanoregulation requires laminA/C, and native topology/lineage results cannot be reduced entirely to terminal mechanical failure." }, { "rank_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Chromatin self-organization with peripheral adhesion", "core_claim": "Heterochromatin compaction and self-association set much organization; envelope contacts provide a boundary condition.", "explains_what_nominal_does_not": "Heterochromatin compaction and self-association set much organization; envelope contacts provide a boundary condition.", "strongest_supporting_evidence": [ "Worm methylation-versus-anchor mutants separate compaction and attachment with little RNA change; enzyme loss can also suppress peripheral euchromatic genes." ], "strongest_contradictory_evidence": [ "Polymer models alone do not establish causality, and endogenous lamin/NET rescues retain a real architectural role." ], "hsef_level_for_this_model": "Ε", "rationale": "Worm methylation-versus-anchor mutants separate compaction and attachment with little RNA change; enzyme loss can also suppress peripheral euchromatic genes. Polymer models alone do not establish causality, and endogenous lamin/NET rescues retain a real architectural role." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Direct global lamina enzymatic repression", "core_claim": "Lamina filaments recruit indispensable enzymatic silencers across LADs and cell states.", "explains_what_nominal_does_not": "Lamina filaments recruit indispensable enzymatic silencers across LADs and cell states.", "strongest_supporting_evidence": [ "Local Drosophila HDAC/lamin effects, SIRT7-L1 regulation and some ectopic tether repression form the strongest support." ], "strongest_contradictory_evidence": [ "Selective recruitment necessity is not isolated; null stem-cell and short-detachment tests, enzyme/position decoupling and active peripheral transcription challenge the global claim." ], "hsef_level_for_this_model": "Γ", "rationale": "Local Drosophila HDAC/lamin effects, SIRT7-L1 regulation and some ectopic tether repression form the strongest support. Selective recruitment necessity is not isolated; null stem-cell and short-detachment tests, enzyme/position decoupling and active peripheral transcription challenge the global claim." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The2026LBR/LAP2 deconvolution (41735607) identifies redundant tethers, with additional B-lamin depletion not enhancing the defined phenotype and only minor RNA changes after72h detachment. The2018TKO/B1 rescue (30201095) directly demonstrates lamin-sensitive topology with matched cell-cycle profiles but no preferential derepression of detached LAD genes. Together they distinguish contextual architectural control from one global filament-dependent silencing route; neither paper alone proves speckle distance is the unique mediator.", "study_separating_rank1_from_rank2": "The2026LBR/LAP2 deconvolution (41735607) identifies redundant tethers, with additional B-lamin depletion not enhancing the defined phenotype and only minor RNA changes after72h detachment. The2018TKO/B1 rescue (30201095) directly demonstrates lamin-sensitive topology with matched cell-cycle profiles but no preferential derepression of detached LAD genes. Together they distinguish contextual architectural control from one global filament-dependent silencing route; neither paper alone proves speckle distance is the unique mediator.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "16878134", "title": "Characterization of the Drosophila melanogaster genome at the nuclear lamina.", "citation": "Pickersgill H, Kalverda B, de Wit E et al. Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nature genetics. 2006.", "doi": "10.1038/ng1852", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16878134/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16878134/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID16878134", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Drosophila lamin-contact genes are silent, late-replicating and depleted of active marks; activation reduces binding.", "what_it_does_not_show": "Genome mapping and activation-linked movement do not identify which direction causes repression.", "confounders_present": [ "Genome mapping and activation-linked movement do not identify which direction causes repression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 2, "pmid": "18463634", "title": "Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions.", "citation": "Guelen L, Pagie L, Brasset E et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008.", "doi": "10.1038/nature06947", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18463634/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18463634/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID18463634", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Human fibroblast maps identify large LADs with low expression and sharp domain boundaries.", "what_it_does_not_show": "Association is not necessary enzymatic repression; linked erratum lacks identifier/details in examined metadata.", "confounders_present": [ "Association is not necessary enzymatic repression; linked erratum lacks identifier/details in examined metadata." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 3, "pmid": "26365489", "title": "Genome-wide maps of nuclear lamina interactions in single human cells.", "citation": "Kind J, Pagie L, de Vries SS et al. Genome-wide maps of nuclear lamina interactions in single human cells. Cell. 2015.", "doi": "10.1016/j.cell.2015.08.040", "pmcid": "PMC4583798", "url": "https://pubmed.ncbi.nlm.nih.gov/26365489/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26365489/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26365489", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-cell human maps show variable and stable LAD contacts inversely linked to gene activity.", "what_it_does_not_show": "Contact consistency and histone correlation do not selectively manipulate lamins or demonstrate transcriptional necessity.", "confounders_present": [ "Contact consistency and histone correlation do not selectively manipulate lamins or demonstrate transcriptional necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 4, "pmid": "36691074", "title": "An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype.", "citation": "Shah PP, Keough KC, Gjoni K et al. An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype. Genome biology. 2023.", "doi": "10.1186/s13059-023-02849-5", "pmcid": "PMC9869549", "url": "https://pubmed.ncbi.nlm.nih.gov/36691074/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36691074/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36691074", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Twelve-cell-type atlas identifies deep and intermediate peripheral chromatin with different expression/accessibility.", "what_it_does_not_show": "Atlas broadens descriptive scope, not causal scope; proximity to lamina differs from direct contact.", "confounders_present": [ "Atlas broadens descriptive scope, not causal scope; proximity to lamina differs from direct contact." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 5, "pmid": "23523135", "title": "Single-cell dynamics of genome-nuclear lamina interactions.", "citation": "Kind J, Pagie L, Ortabozkoyun H et al. Single-cell dynamics of genome-nuclear lamina interactions. Cell. 2013.", "doi": "10.1016/j.cell.2013.02.028", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23523135/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23523135/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23523135", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Single-cell LAD contacts are intermittent, reshuffled after mitosis and regulated by G9a.", "what_it_does_not_show": "H3K9 methylation may regulate anchoring; contact-memory assay does not establish lamina recruitment as the obligatory source of silencing.", "confounders_present": [ "H3K9 methylation may regulate anchoring; contact-memory assay does not establish lamina recruitment as the obligatory source of silencing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 6, "pmid": "18272965", "title": "Transcriptional repression mediated by repositioning of genes to the nuclear lamina.", "citation": "Reddy KL, Zullo JM, Bertolino E et al. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature. 2008.", "doi": "10.1038/nature06727", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18272965/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18272965/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID18272965", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic cellular tethering", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Inducible INM tethering can reposition and repress selected chromosomal regions after mitosis.", "what_it_does_not_show": "Ectopic targeting tests sufficiency of the construct/context, not necessity of endogenous lamin-mediated repression genome-wide.", "confounders_present": [ "Ectopic targeting tests sufficiency of the construct/context, not necessity of endogenous lamin-mediated repression genome-wide." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 7, "pmid": "18195101", "title": "A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence.", "citation": "Kumaran RI, Spector DL. A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence. The Journal of cell biology. 2008.", "doi": "10.1083/jcb.200706060", "pmcid": "PMC2213611", "url": "https://pubmed.ncbi.nlm.nih.gov/18195101/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18195101/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID18195101", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph17, 1:Results:paragraph20. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic cellular tethering", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Lamin-B1-tethered peripheral transgene array retains inducible transcription and similar induction kinetics.", "what_it_does_not_show": "Large multicopy synthetic array and strong Tet activation are not every native promoter; peripheral positioning is not universally sufficient to silence.", "confounders_present": [ "Large multicopy synthetic array and strong Tet activation are not every native promoter; peripheral positioning is not universally sufficient to silence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 8, "pmid": "30982597", "title": "Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs.", "citation": "Leemans C, van der Zwalm MCH, Brueckner L et al. Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs. Cell. 2019.", "doi": "10.1016/j.cell.2019.03.009", "pmcid": "PMC6506275", "url": "https://pubmed.ncbi.nlm.nih.gov/30982597/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30982597/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30982597", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic cellular reporter", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Promoters moved from LADs and reporters inserted across chromatin show promoter/local-context-dependent repression and escapers.", "what_it_does_not_show": "Relocation/reporter designs establish contextual sufficiency, not lamina filament or recruited-enzyme necessity for all native LAD genes.", "confounders_present": [ "Relocation/reporter designs establish contextual sufficiency, not lamina filament or recruited-enzyme necessity for all native LAD genes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "39322756", "title": "Chromatin protein complexes involved in gene repression in lamina-associated domains.", "citation": "Manzo SG, Mazouzi A, Leemans C et al. Chromatin protein complexes involved in gene repression in lamina-associated domains. The EMBO journal. 2024.", "doi": "10.1038/s44318-024-00214-1", "pmcid": "PMC11535540", "url": "https://pubmed.ncbi.nlm.nih.gov/39322756/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39322756/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39322756", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph14, 1:Results:paragraph22, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular with integrated reporters", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "LAD reporter screens identify many chromatin regulators and few envelope hits; LMNB1 is modest in one LAD and null in another; native-gene CRISPRi tests NELF.", "what_it_does_not_show": "Essential proteins and redundancy may be missed; matched-expression analysis reduces apparent LAD preference. Native NELF effect does not prove its recruitment by lamina.", "confounders_present": [ "Essential proteins and redundancy may be missed; matched-expression analysis reduces apparent LAD preference. Native NELF effect does not prove its recruitment by lamina." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Two LAD reporter screens share HAP1 background and selection failure modes; essential/redundant proteins may be missed." ] }, { "n": 10, "pmid": "23226217", "title": "Role of histone deacetylases in gene regulation at nuclear lamina.", "citation": "Milon BC, Cheng H, Tselebrovsky MV et al. Role of histone deacetylases in gene regulation at nuclear lamina. PloS one. 2012.", "doi": "10.1371/journal.pone.0049692", "pmcid": "PMC3511463", "url": "https://pubmed.ncbi.nlm.nih.gov/23226217/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23226217/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23226217", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results and Discussion:paragraph0, 2:Results and Discussion:paragraph2, 2:Results and Discussion:paragraph4, 2:Results and Discussion:paragraph6, 2:Results and Discussion:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Drosophila lamin and HDAC knockdowns identify local chromatin/transcription effects; HDAC1 silences while HDAC3 contributes anchoring.", "what_it_does_not_show": "HDAC1 acts beyond tightly bound genes and changes growth modestly; selective lamina-HDAC interaction loss/rescue is absent. Local support is not global enzyme necessity.", "confounders_present": [ "HDAC1 acts beyond tightly bound genes and changes growth modestly; selective lamina-HDAC interaction loss/rescue is absent. Local support is not global enzyme necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 11, "pmid": "36833261", "title": "Gene Regulatory Interactions at Lamina-Associated Domains.", "citation": "Madsen-Østerbye J, Abdelhalim M, Pickering SH et al. Gene Regulatory Interactions at Lamina-Associated Domains. Genes. 2023.", "doi": "10.3390/genes14020334", "pmcid": "PMC9957430", "url": "https://pubmed.ncbi.nlm.nih.gov/36833261/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36833261/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36833261", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Active in-LAD genes contact enhancers; A-type but not B1 lamins contribute to repression near one active-region border.", "what_it_does_not_show": "Limited loci and differentiation state; not every LAD is silent or regulated identically, and contact alone is not enhancer causality.", "confounders_present": [ "Limited loci and differentiation state; not every LAD is silent or regulated identically, and contact alone is not enhancer causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 12, "pmid": "27264872", "title": "Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis.", "citation": "Robson MI, de Las Heras JI, Czapiewski R et al. Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis. Molecular cell. 2016.", "doi": "10.1016/j.molcel.2016.04.035", "pmcid": "PMC4914829", "url": "https://pubmed.ncbi.nlm.nih.gov/27264872/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27264872/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27264872", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Muscle-specific NET depletion/repositioning changes selected developmental-gene repression and myogenesis.", "what_it_does_not_show": "NETs rather than lamin filaments are targeted; combined loss affects differentiation. Tissue-specific architecture does not establish a global lamin mechanism.", "confounders_present": [ "NETs rather than lamin filaments are targeted; combined loss affects differentiation. Tissue-specific architecture does not establish a global lamin mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 13, "pmid": "34023908", "title": "The nuclear periphery is a scaffold for tissue-specific enhancers.", "citation": "Smith CL, Poleshko A, Epstein JA. The nuclear periphery is a scaffold for tissue-specific enhancers. Nucleic acids research. 2021.", "doi": "10.1093/nar/gkab392", "pmcid": "PMC8216274", "url": "https://pubmed.ncbi.nlm.nih.gov/34023908/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34023908/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34023908", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Peripheral H3K9me2-only enhancer domains have limited LaminB interaction and differ from LADs.", "what_it_does_not_show": "Poised enhancer mapping is descriptive; nuclear periphery cannot be treated as synonymous with lamin contact or complete inactivity.", "confounders_present": [ "Poised enhancer mapping is descriptive; nuclear periphery cannot be treated as synonymous with lamin contact or complete inactivity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 14, "pmid": "29750270", "title": "Peripheral re-localization of constitutive heterochromatin advances its replication timing and impairs maintenance of silencing marks.", "citation": "Heinz KS, Casas-Delucchi CS, Török T et al. Peripheral re-localization of constitutive heterochromatin advances its replication timing and impairs maintenance of silencing marks. Nucleic acids research. 2018.", "doi": "10.1093/nar/gky368", "pmcid": "PMC6158597", "url": "https://pubmed.ncbi.nlm.nih.gov/29750270/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29750270/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29750270", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic cellular tethering", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Peripheral relocation advances heterochromatin replication and impairs silencing-mark maintenance.", "what_it_does_not_show": "Synthetic repositioning and replication endpoints do not prove endogenous transcriptional output; it opposes uniform repressive direction.", "confounders_present": [ "Synthetic repositioning and replication endpoints do not prove endogenous transcriptional output; it opposes uniform repressive direction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 15, "pmid": "22116031", "title": "Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells.", "citation": "Kim Y, Sharov AA, McDole K et al. Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. Science (New York, N.Y.). 2011.", "doi": "10.1126/science.1211222", "pmcid": "PMC3306219", "url": "https://pubmed.ncbi.nlm.nih.gov/22116031/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22116031/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MOUSE_LAMIN_NULL_ESC_SERIES", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Main text:paragraph3, 1:Main text:paragraph4, 1:Main text:paragraph9. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular and animal in vivo", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "B-lamin-null ESCs retain self-renewal and differentiation; expression changes do not correlate with lamin-bound promoters, while organogenesis requires lamins.", "what_it_does_not_show": "Mouse ESC/TE contexts differ from tissues and chronic compensation is possible; lamin absence is not absence of all envelope tethers.", "confounders_present": [ "Mouse ESC/TE contexts differ from tissues and chronic compensation is possible; lamin absence is not absence of all envelope tethers." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 16, "pmid": "25784758", "title": "Nuclear lamins are not required for lamina-associated domain organization in mouse embryonic stem cells.", "citation": "Amendola M, van Steensel B. Nuclear lamins are not required for lamina-associated domain organization in mouse embryonic stem cells. EMBO reports. 2015.", "doi": "10.15252/embr.201439789", "pmcid": "PMC4428043", "url": "https://pubmed.ncbi.nlm.nih.gov/25784758/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25784758/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25784758", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Essentially all-lamin removal leaves genome-wide emerin-contact organization detectable in mouse ESCs.", "what_it_does_not_show": "Emerin marks envelope contact, not every mesoscale interaction or functional output; redundancy and cell state remain.", "confounders_present": [ "Emerin marks envelope contact, not every mesoscale interaction or functional output; redundancy and cell state remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Mouse ESC lamin-null paradigm and DamID envelope-contact measurement shared with parts of the field." ] }, { "n": 17, "pmid": "30201095", "title": "Lamins Organize the Global Three-Dimensional Genome from the Nuclear Periphery.", "citation": "Zheng X, Hu J, Yue S et al. Lamins Organize the Global Three-Dimensional Genome from the Nuclear Periphery. Molecular cell. 2018.", "doi": "10.1016/j.molcel.2018.05.017", "pmcid": "PMC6886264", "url": "https://pubmed.ncbi.nlm.nih.gov/30201095/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30201095/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MOUSE_LAMIN_NULL_ESC_SERIES", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph4, 1:Results:paragraph15, 1:Results:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Lamin TKO changes selected LAD/topological interactions and B1 restoration partly reverses topology with matched cell-cycle profiles.", "what_it_does_not_show": "Detached LAD genes are not preferentially upregulated; RNA changes correlate with altered interactions but selective topology-to-transcription mediation is incomplete. Re-expression also creates non-native interactions.", "confounders_present": [ "Detached LAD genes are not preferentially upregulated; RNA changes correlate with altered interactions but selective topology-to-transcription mediation is incomplete. Re-expression also creates non-native interactions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Same lineage/model family as2011lamin-null ESC work; complementary topology/RNA assays are not separate studies." ] }, { "n": 18, "pmid": "41205174", "title": "Nuclear-lamin-guided plastic positioning and folding of the human genome.", "citation": "Wang Z, Ji Q, Liu Z et al. Nuclear-lamin-guided plastic positioning and folding of the human genome. Cell reports. 2025.", "doi": "10.1016/j.celrep.2025.116529", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41205174/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41205174/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41205174", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Human lamin KO maps state-dependent genome/speckle disorganization and lower transcription; WT-A versus SON-binding-defective mutant rescue differs.", "what_it_does_not_show": "Whole-protein chronic loss and reduced global transcription/homeostasis limit specificity; original abstract only, not audited Methods or matched-rescue levels.", "confounders_present": [ "Whole-protein chronic loss and reduced global transcription/homeostasis limit specificity; original abstract only, not audited Methods or matched-rescue levels." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Human knockout/homeostasis/speckle and rescue readouts share one system; body/supplements not examined." ] }, { "n": 19, "pmid": "34058264", "title": "Decreased Lamin B1 Levels Affect Gene Positioning and Expression in Postmitotic Neurons.", "citation": "Noguchi A, Ito K, Uosaki Y et al. Decreased Lamin B1 Levels Affect Gene Positioning and Expression in Postmitotic Neurons. Neuroscience research. 2021.", "doi": "10.1016/j.neures.2021.05.011", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34058264/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34058264/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34058264", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal neuronal culture with overexpression", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LaminB1 decline accompanies neuronal locus movement and ectopic B1 blocks movement/Egr3 expression.", "what_it_does_not_show": "Overexpression demonstrates a construct effect, not endogenous-B1 necessity or global silencing; maturation is a concurrent change.", "confounders_present": [ "Overexpression demonstrates a construct effect, not endogenous-B1 necessity or global silencing; maturation is a concurrent change." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 20, "pmid": "31117946", "title": "Lamin A/C and Emerin depletion impacts chromatin organization and dynamics in the interphase nucleus.", "citation": "Ranade D, Pradhan R, Jayakrishnan M et al. Lamin A/C and Emerin depletion impacts chromatin organization and dynamics in the interphase nucleus. BMC molecular and cell biology. 2019.", "doi": "10.1186/s12860-019-0192-5", "pmcid": "PMC6532135", "url": "https://pubmed.ncbi.nlm.nih.gov/31117946/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31117946/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31117946", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "LaminA/emerin depletion changes actin/NM1, chromatin mobility, locus positioning and selected expression; motor/actin interventions restore mobility.", "what_it_does_not_show": "Cytoskeletal alterations provide an alternative mediator; mobility rescue is not necessarily transcriptional rescue or direct lamina silencing.", "confounders_present": [ "Cytoskeletal alterations provide an alternative mediator; mobility rescue is not necessarily transcriptional rescue or direct lamina silencing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "30862957", "title": "Nuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila.", "citation": "Ulianov SV, Doronin SA, Khrameeva EE et al. Nuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila. Nature communications. 2019.", "doi": "10.1038/s41467-019-09185-y", "pmcid": "PMC6414625", "url": "https://pubmed.ncbi.nlm.nih.gov/30862957/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30862957/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30862957", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Drosophila NL disruption changes LAD compaction/acetylation/background expression and global contacts.", "what_it_does_not_show": "Chronic RNAi and polymer simulations do not isolate a unique enzymatic silencing route; organism/cell context restricts inference.", "confounders_present": [ "Chronic RNAi and polymer simulations do not isolate a unique enzymatic silencing route; organism/cell context restricts inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 22, "pmid": "29529026", "title": "Argonaute2 and LaminB modulate gene expression by controlling chromatin topology.", "citation": "Nazer E, Dale RK, Chinen M et al. Argonaute2 and LaminB modulate gene expression by controlling chromatin topology. PLoS genetics. 2018.", "doi": "10.1371/journal.pgen.1007276", "pmcid": "PMC5864089", "url": "https://pubmed.ncbi.nlm.nih.gov/29529026/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29529026/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29529026", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function. Nature communications. 2022.", "doi": "10.1038/s41467-022-34366-7", "pmcid": "PMC9636150", "url": "https://pubmed.ncbi.nlm.nih.gov/36333314/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36333314/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36333314", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph27, 1:Results:paragraph41, 1:Results:paragraph43. 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Disease point mutations differ from null." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 24, "pmid": "32208162", "title": "Phosphorylated Lamin A/C in the Nuclear Interior Binds Active Enhancers Associated with Abnormal Transcription in Progeria.", "citation": "Ikegami K, Secchia S, Almakki O et al. Phosphorylated Lamin A/C in the Nuclear Interior Binds Active Enhancers Associated with Abnormal Transcription in Progeria. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Interior phospho-laminA/C binds active enhancers rather than LADs, with altered enhancer/expression patterns in progeria.", "what_it_does_not_show": "Binding and disease association do not demonstrate direct enhancer causality; intranuclear lamins are distinct from peripheral tethering.", "confounders_present": [ "Binding and disease association do not demonstrate direct enhancer causality; intranuclear lamins are distinct from peripheral tethering." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 25, "pmid": "31988151", "title": "Lamin A/C modulates spatial organization and function of the Hsp70 gene locus via nuclear myosin I.", "citation": "Pradhan R, Nallappa MJ, Sengupta K. Lamin A/C modulates spatial organization and function of the Hsp70 gene locus via nuclear myosin I. Journal of cell science. 2020.", "doi": "10.1242/jcs.236265", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31988151/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31988151/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31988151", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "LaminA/C and nuclear myosin are required for heat-shock Hsp70 locus repositioning, speckle organization and induction.", "what_it_does_not_show": "Inducible activation rather than repression; motor, stress and structure effects are intertwined and locus-specific.", "confounders_present": [ "Inducible activation rather than repression; motor, stress and structure effects are intertwined and locus-specific." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 26, "pmid": "23374351", "title": "LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation.", "citation": "Solovei I, Wang AS, Thanisch K et al. LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell. 2013.", "doi": "10.1016/j.cell.2013.01.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23374351/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23374351/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23374351", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo and endogenous cellular", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "LBR and laminA/C sequentially/redundantly tether heterochromatin; combined absence inverts architecture and tether losses have opposite myoblast expression effects.", "what_it_does_not_show": "Redundant cell-specific NE network rather than one universal lamin repression pathway; topology inversion is not necessarily transcriptional loss.", "confounders_present": [ "Redundant cell-specific NE network rather than one universal lamin repression pathway; topology inversion is not necessarily transcriptional loss." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 27, "pmid": "41735607", "title": "LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis.", "citation": "Lewis R, Sinigiani V, Maziak N et al. LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis. Nature cell biology. 2026.", "doi": "10.1038/s41556-025-01822-7", "pmcid": "PMC12992122", "url": "https://pubmed.ncbi.nlm.nih.gov/41735607/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41735607/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41735607", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph12, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph32. 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Antagonistic contributions of A-type and B-type lamins to LBR localization and dynamics. Nucleus (Austin, Tex.). 2026.", "doi": "10.1080/19491034.2026.2673721", "pmcid": "PMC13192086", "url": "https://pubmed.ncbi.nlm.nih.gov/42153377/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42153377/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID41757046" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42153377", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular with re-expression", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Lamin isoform re-expression in null fibroblasts differentially alters LBR anchorage and mobility.", "what_it_does_not_show": "Ectopic expression and phosphorylation effects define architecture, not a transcriptional endpoint or universal direct gene repression; preprint not counted separately.", "confounders_present": [ "Ectopic expression and phosphorylation effects define architecture, not a transcriptional endpoint or universal direct gene repression; preprint not counted separately." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 29, "pmid": "28056360", "title": "Nuclear envelope localization of LEMD2 is developmentally dynamic and lamin A/C dependent yet insufficient for heterochromatin tethering.", "citation": "Thanisch K, Song C, Engelkamp D et al. Nuclear envelope localization of LEMD2 is developmentally dynamic and lamin A/C dependent yet insufficient for heterochromatin tethering. Differentiation; research in biological diversity. 2017.", "doi": "10.1016/j.diff.2016.12.002", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28056360/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28056360/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28056360", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo with transgene", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "LEMD2 localization depends on laminA/C but LEMD2 alone or with laminC fails to restore peripheral heterochromatin in rods.", "what_it_does_not_show": "Negative synthetic rescue tests one candidate network component; does not exclude other redundant tethers or all roles for lamins.", "confounders_present": [ "Negative synthetic rescue tests one candidate network component; does not exclude other redundant tethers or all roles for lamins." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 30, "pmid": "24209742", "title": "The human protein PRR14 tethers heterochromatin to the nuclear lamina during interphase and mitotic exit.", "citation": "Poleshko A, Mansfield KM, Burlingame CC et al. The human protein PRR14 tethers heterochromatin to the nuclear lamina during interphase and mitotic exit. Cell reports. 2013.", "doi": "10.1016/j.celrep.2013.09.024", "pmcid": "PMC3867587", "url": "https://pubmed.ncbi.nlm.nih.gov/24209742/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24209742/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PRR14_TETHER_SERIES", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "PRR14 links HP1-marked chromatin and lamina with ordered mitotic reassembly.", "what_it_does_not_show": "Anchoring/localization function is not demonstrated necessary global transcriptional silencing.", "confounders_present": [ "Anchoring/localization function is not demonstrated necessary global transcriptional silencing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 31, "pmid": "32317397", "title": "The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting.", "citation": "Dunlevy KL, Medvedeva V, Wilson JE et al. The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting. Journal of cell science. 2020.", "doi": "10.1242/jcs.240416", "pmcid": "PMC7272351", "url": "https://pubmed.ncbi.nlm.nih.gov/32317397/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32317397/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PRR14_TETHER_SERIES", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "cellular modular construct", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "PRR14 domain dissection separates chromatin and lamina binding with phosphorylation regulation.", "what_it_does_not_show": "Construct localization sufficiency and dynamics do not prove natural gene-output dependence.", "confounders_present": [ "Construct localization sufficiency and dynamics do not prove natural gene-output dependence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 32, "pmid": "36633363", "title": "PRR14 organizes H3K9me3-modified heterochromatin at the nuclear lamina.", "citation": "Kiseleva AA, Cheng YC, Smith CL et al. PRR14 organizes H3K9me3-modified heterochromatin at the nuclear lamina. Nucleus (Austin, Tex.). 2023.", "doi": "10.1080/19491034.2023.2165602", "pmcid": "PMC9839372", "url": "https://pubmed.ncbi.nlm.nih.gov/36633363/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36633363/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PRR14_TETHER_SERIES", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular with constructs", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "PRR14/HP1 interactions dynamically organize H3K9me3 chromatin at lamina independent of mitosis.", "what_it_does_not_show": "Imaging and HP1 domain manipulation define tether biology; endogenous transcriptional mediation remains untested in the examined abstract.", "confounders_present": [ "Imaging and HP1 domain manipulation define tether biology; endogenous transcriptional mediation remains untested in the examined abstract." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 33, "pmid": "26607792", "title": "Perinuclear Anchoring of H3K9-Methylated Chromatin Stabilizes Induced Cell Fate in C. elegans Embryos.", "citation": "Gonzalez-Sandoval A, Towbin BD, Kalck V et al. Perinuclear Anchoring of H3K9-Methylated Chromatin Stabilizes Induced Cell Fate in C. elegans Embryos. Cell. 2015.", "doi": "10.1016/j.cell.2015.10.066", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26607792/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26607792/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26607792", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "CEC4 is necessary for endogenous worm heterochromatin anchoring but not transcriptional repression, while affecting induced cell-fate commitment.", "what_it_does_not_show": "CEC4 localizes independently of nuclear lamin; ectopic muscle induction is a restricted cell-fate test, not global natural differentiation necessity.", "confounders_present": [ "CEC4 localizes independently of nuclear lamin; ectopic muscle induction is a restricted cell-fate test, not global natural differentiation necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 34, "pmid": "31118512", "title": "Active chromatin marks drive spatial sequestration of heterochromatin in C. elegans nuclei.", "citation": "Cabianca DS, Muñoz-Jiménez C, Kalck V et al. Active chromatin marks drive spatial sequestration of heterochromatin in C. elegans nuclei. Nature. 2019.", "doi": "10.1038/s41586-019-1243-y", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31118512/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31118512/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31118512", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "MRG1/CEC4 and CBP1/ATF8 epistasis separates active-chromatin retention from direct peripheral anchoring in worms.", "what_it_does_not_show": "Distinct embryonic/differentiated contexts and broad acetylation changes; this is not a lamina-recruited silencer mechanism.", "confounders_present": [ "Distinct embryonic/differentiated contexts and broad acetylation changes; this is not a lamina-recruited silencer mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 35, "pmid": "32385148", "title": "Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring.", "citation": "Bian Q, Anderson EC, Yang Q et al. Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring. Proceedings of the National Academy of Sciences of the United States of America. 2020.", "doi": "10.1073/pnas.2002068117", "pmcid": "PMC7261013", "url": "https://pubmed.ncbi.nlm.nih.gov/32385148/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32385148/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32385148", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "H3K9 methyltransferase and CEC4 mutants impair compartments through separable compaction and anchoring mechanisms with little expression change.", "what_it_does_not_show": "Gene expression remains largely intact despite compartment switching; heterochromatin self-association and anchoring cannot be equated with lamin-global repression.", "confounders_present": [ "Gene expression remains largely intact despite compartment switching; heterochromatin self-association and anchoring cannot be equated with lamin-global repression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 36, "pmid": "32139421", "title": "Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model.", "citation": "Harr JC, Schmid CD, Muñoz-Jiménez C et al. Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model. Genes & development. 2020.", "doi": "10.1101/gad.332213.119", "pmcid": "PMC7111258", "url": "https://pubmed.ncbi.nlm.nih.gov/32139421/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32139421/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32139421", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo disease model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CEC4 ablation rescues lamin-mutant worm positioning, some transcription and muscle function.", "what_it_does_not_show": "Mutant forced disease model scope is restricted; relieving attachment helps, opposing a uniform more-tethering-equals-healthier-repression model.", "confounders_present": [ "Mutant forced disease model scope is restricted; relieving attachment helps, opposing a uniform more-tethering-equals-healthier-repression model." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 37, "pmid": "40335054", "title": "Nuclear deformability depends on H3K9-methylated heterochromatin anchorage to the nuclear periphery in Caenorhabditis elegans.", "citation": "Gregory EF, Luxton GWG, Starr DA. Nuclear deformability depends on H3K9-methylated heterochromatin anchorage to the nuclear periphery in Caenorhabditis elegans. Genetics. 2025.", "doi": "10.1093/genetics/iyaf086", "pmcid": "PMC12239201", "url": "https://pubmed.ncbi.nlm.nih.gov/40335054/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40335054/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40335054", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CEC4-mediated anchoring contributes to nuclear migration/deformability in LINC-defective worms and lamin-stabilizing mutation rescues.", "what_it_does_not_show": "Mechanical phenotype, conditional LINC background and gene-output absence; anchoring has a mechanical role rather than proof of global transcriptional primacy.", "confounders_present": [ "Mechanical phenotype, conditional LINC background and gene-output absence; anchoring has a mechanical role rather than proof of global transcriptional primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 38, "pmid": "42538931", "title": "Nuclear envelope-dependent heterochromatin positioning gates the timing of nucleolar assembly in the early embryo.", "citation": "Ding X, Wang G, Elnatan D et al. Nuclear envelope-dependent heterochromatin positioning gates the timing of nucleolar assembly in the early embryo. bioRxiv : the preprint server for biology. 2026.", "doi": "10.64898/2026.07.20.739428", "pmcid": "PMC13419420", "url": "https://pubmed.ncbi.nlm.nih.gov/42538931/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42538931/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42538931", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LINC/lamin depletion alters early nucleolar timing, with CEC4 epistasis and heterochromatin spatial changes.", "what_it_does_not_show": "Embryonic assembly phenotype differs from LAD transcription; nuclear-envelope perturbations have multiple structural/cell-cycle functions.", "confounders_present": [ "Embryonic assembly phenotype differs from LAD transcription; nuclear-envelope perturbations have multiple structural/cell-cycle functions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 39, "pmid": "14755334", "title": "Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.", "citation": "Lammerding J, Schulze PC, Takahashi T et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. The Journal of clinical investigation. 2004.", "doi": "10.1172/JCI19670", "pmcid": "PMC324542", "url": "https://pubmed.ncbi.nlm.nih.gov/14755334/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14755334/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID14755334", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Lmna-null fibroblasts show impaired mechanical resistance, survival under strain and mechanically activated NFkB transcription.", "what_it_does_not_show": "Functional mechanics is a real lamin contribution; viability and cytoskeletal signaling must be separated from direct LAD repression.", "confounders_present": [ "Functional mechanics is a real lamin contribution; viability and cytoskeletal signaling must be separated from direct LAD repression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 40, "pmid": "23990565", "title": "Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation.", "citation": "Swift J, Ivanovska IL, Buxboim A et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science (New York, N.Y.). 2013.", "doi": "10.1126/science.1240104", "pmcid": "PMC3976548", "url": "https://pubmed.ncbi.nlm.nih.gov/23990565/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23990565/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23990565", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular and tissue observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LaminA levels track tissue stiffness and graded manipulation modifies matrix-directed differentiation and receptor trafficking.", "what_it_does_not_show": "Stiffness-response feedback and level manipulation are not direct enzymatic repression or complete separation of mechanics from regulation.", "confounders_present": [ "Stiffness-response feedback and level manipulation are not direct enzymatic repression or complete separation of mechanics from regulation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 41, "pmid": "23644458", "title": "Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics.", "citation": "Ho CY, Jaalouk DE, Vartiainen MK et al. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature. 2013.", "doi": "10.1038/nature12105", "pmcid": "PMC3666313", "url": "https://pubmed.ncbi.nlm.nih.gov/23644458/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23644458/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23644458", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular and animal genetic", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Lamin mutants alter actin/MKL1-SRF signaling and emerin expression restores trafficking and actin dynamics.", "what_it_does_not_show": "Ectopic rescue and mechanical/nuclear-actin mediation do not establish peripheral chromatin recruitment as the cause.", "confounders_present": [ "Ectopic rescue and mechanical/nuclear-actin mediation do not establish peripheral chromatin recruitment as the cause." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 42, "pmid": "34205295", "title": "Lamin A/C Is Dispensable to Mechanical Repression of Adipogenesis.", "citation": "Goelzer M, Dudakovic A, Olcum M et al. Lamin A/C Is Dispensable to Mechanical Repression of Adipogenesis. International journal of molecular sciences. 2021.", "doi": "10.3390/ijms22126580", "pmcid": "PMC8234021", "url": "https://pubmed.ncbi.nlm.nih.gov/34205295/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34205295/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34205295", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "LaminA/C knockdown leaves vibration-induced adipogenesis repression and focal-adhesion activation intact despite nuclear mechanical changes.", "what_it_does_not_show": "Specific mechanical protocol and partial depletion restrict generalization; not every mechanotransduction response requires A-type lamin.", "confounders_present": [ "Specific mechanical protocol and partial depletion restrict generalization; not every mechanotransduction response requires A-type lamin." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 43, "pmid": "41126185", "title": "Lamin A/C protects chromatin accessibility during mechanical loading in human skeletal muscle.", "citation": "Jabre S, Cherchame E, Pinzón N et al. Lamin A/C protects chromatin accessibility during mechanical loading in human skeletal muscle. Cell communication and signaling : CCS. 2025.", "doi": "10.1186/s12964-025-02437-z", "pmcid": "PMC12542426", "url": "https://pubmed.ncbi.nlm.nih.gov/41126185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41126185/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41126185", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous human cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LaminA/C-deficient human myotubes show amplified stretch-related deformation, accessibility and transcriptional stress responses.", "what_it_does_not_show": "Mechanical challenge and damage responses are inseparable in this design; ATAC/marks alone would not establish regulation, while accompanying RNA still lacks direct tether specificity.", "confounders_present": [ "Mechanical challenge and damage responses are inseparable in this design; ATAC/marks alone would not establish regulation, while accompanying RNA still lacks direct tether specificity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 44, "pmid": "38718107", "title": "Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.", "citation": "Sikder K, Phillips E, Zhong Z et al. Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy. Science advances. 2024.", "doi": "10.1126/sciadv.adh0798", "pmcid": "PMC11078192", "url": "https://pubmed.ncbi.nlm.nih.gov/38718107/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38718107/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36824975" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38718107", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Adult cardiomyocyte Lmna deletion triggers perinuclear stress before cardiac dysfunction; stress/autophagy drugs delay disease.", "what_it_does_not_show": "Therapeutic benefit identifies a downstream stress pathway, not universal LAD repression; mutant disease model and pleiotropic drugs remain.", "confounders_present": [ "Therapeutic benefit identifies a downstream stress pathway, not universal LAD repression; mutant disease model and pleiotropic drugs remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 45, "pmid": "23019125", "title": "Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response.", "citation": "Osorio FG, Bárcena C, Soria-Valles C et al. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response. Genes & development. 2012.", "doi": "10.1101/gad.197954.112", "pmcid": "PMC3475803", "url": "https://pubmed.ncbi.nlm.nih.gov/23019125/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23019125/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23019125", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo disease model", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Two prelamin/progeria models show ATM/NEMO/NFkB inflammation, with genetic/pharmacologic blockade improving disease and survival.", "what_it_does_not_show": "Accelerated-aging genetic models do not establish ordinary global gene silencing; damage-signaling mechanism competes with direct repression.", "confounders_present": [ "Accelerated-aging genetic models do not establish ordinary global gene silencing; damage-signaling mechanism competes with direct repression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 46, "pmid": "31576060", "title": "The NSL complex maintains nuclear architecture stability via lamin A/C acetylation.", "citation": "Karoutas A, Szymanski W, Rausch T et al. The NSL complex maintains nuclear architecture stability via lamin A/C acetylation. Nature cell biology. 2019.", "doi": "10.1038/s41556-019-0397-z", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31576060/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31576060/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36849559" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31576060", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MOF/NSL loss alters lamin acetylation and nuclear stability; HDAC inhibition or acetylation mimic rescues abnormal architecture.", "what_it_does_not_show": "Broad chromatin/architecture effects and ectopic rescue; transcription loss in nuclear abnormalities may reflect global damage. Linked2019correction details not audited.", "confounders_present": [ "Broad chromatin/architecture effects and ectopic rescue; transcription loss in nuclear abnormalities may reflect global damage. Linked2019correction details not audited." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 47, "pmid": "31226208", "title": "SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina.", "citation": "Vazquez BN, Thackray JK, Simonet NG et al. SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina. Nucleic acids research. 2019.", "doi": "10.1093/nar/gkz519", "pmcid": "PMC6735864", "url": "https://pubmed.ncbi.nlm.nih.gov/31226208/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31226208/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31226208", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "SIRT7 depletion increases L1 expression/retrotransposition and H3K18 acetylation with impaired lamin association.", "what_it_does_not_show": "L1 repeat subset and enzyme-to-anchoring direction; selective recruitment-defective interaction rescue is needed to establish lamina-dependent repression rather than parallel effects.", "confounders_present": [ "L1 repeat subset and enzyme-to-anchoring direction; selective recruitment-defective interaction rescue is needed to establish lamina-dependent repression rather than parallel effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 48, "pmid": "32813328", "title": "Lamin A safeguards the m6 A methylase METTL14 nuclear speckle reservoir to prevent cellular senescence.", "citation": "Zhang J, Ao Y, Zhang Z et al. Lamin A safeguards the m6 A methylase METTL14 nuclear speckle reservoir to prevent cellular senescence. Aging cell. 2020.", "doi": "10.1111/acel.13215", "pmcid": "PMC7576246", "url": "https://pubmed.ncbi.nlm.nih.gov/32813328/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32813328/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32813328", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous cellular with overexpression", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LaminA deficiency destabilizes speckle METTL3/14 reservoir and METTL14 overexpression reduces senescence markers.", "what_it_does_not_show": "RNA methylation reservoir and senescence models are not direct LAD silencing or organismal healthspan; overexpression/markers retain caps.", "confounders_present": [ "RNA methylation reservoir and senescence models are not direct LAD silencing or organismal healthspan; overexpression/markers retain caps." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 49, "pmid": "32805188", "title": "Identification of Genes and Pathways Regulated by Lamin A in Heart.", "citation": "Coste Pradas J, Auguste G, Matkovich SJ et al. Identification of Genes and Pathways Regulated by Lamin A in Heart. Journal of the American Heart Association. 2020.", "doi": "10.1161/JAHA.119.015690", "pmcid": "PMC7660829", "url": "https://pubmed.ncbi.nlm.nih.gov/32805188/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32805188/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32805188", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Lmna-null heart transcriptome alterations precede dysfunction and AAV-lamin rescue restores many genes with improved function/survival.", "what_it_does_not_show": "Whole-protein rescue restores mechanics and transcription together; upstream regulator inference does not demonstrate direct peripheral silencer recruitment.", "confounders_present": [ "Whole-protein rescue restores mechanics and transcription together; upstream regulator inference does not demonstrate direct peripheral silencer recruitment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 50, "pmid": "33396724", "title": "Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth.", "citation": "Owens DJ, Messéant J, Moog S et al. Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth. International journal of molecular sciences. 2020.", "doi": "10.3390/ijms22010306", "pmcid": "PMC7795708", "url": "https://pubmed.ncbi.nlm.nih.gov/33396724/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33396724/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33396724", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human cellular and animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "LMNA-CMD mutations impair strain/YAP response and muscle growth with functional overload; related EDMD models differ.", "what_it_does_not_show": "Disease allele/lineage and mechanics specificity map context, not a global transcriptionally repressive lamina role.", "confounders_present": [ "Disease allele/lineage and mechanics specificity map context, not a global transcriptionally repressive lamina role." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 51, "pmid": "38284866", "title": "Lamin A/C mediates microglial activation by modulating cell proliferation and immune response.", "citation": "Liu H, Liu X, Luo S et al. Lamin A/C mediates microglial activation by modulating cell proliferation and immune response. Journal of neuroscience research. 2024.", "doi": "10.1002/jnr.25263", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38284866/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38284866/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38284866", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal cellular and endogenous cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Lmna loss suppresses stimulated microglial proliferation/activation with proteomic and immune changes.", "what_it_does_not_show": "Proliferation and response-state differences may mediate RNA/protein output; mechanotransduction is proposed, not selectively proved.", "confounders_present": [ "Proliferation and response-state differences may mediate RNA/protein output; mechanotransduction is proposed, not selectively proved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 52, "pmid": "31372995", "title": "Lamin A/C deficiency in CD4+ T-cells enhances regulatory T-cells and prevents inflammatory bowel disease.", "citation": "Toribio-Fernández R, Herrero-Fernandez B, Zorita V et al. Lamin A/C deficiency in CD4+ T-cells enhances regulatory T-cells and prevents inflammatory bowel disease. The Journal of pathology. 2019.", "doi": "10.1002/path.5332", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31372995/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31372995/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31372995", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo and cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "T-cell Lmna loss shifts Treg/Th1 differentiation and lessens adoptive-transfer colitis with TF chromatin changes.", "what_it_does_not_show": "Forced recipient model tests transferred cells, not spontaneous disease; lineage and RA environment matter and no global LAD mechanism is isolated.", "confounders_present": [ "Forced recipient model tests transferred cells, not spontaneous disease; lineage and RA environment matter and no global LAD mechanism is isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 53, "pmid": "33514739", "title": "The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization.", "citation": "Ramirez-Martinez A, Zhang Y, Chen K et al. The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization. Nature communications. 2021.", "doi": "10.1038/s41467-021-20987-x", "pmcid": "PMC7846557", "url": "https://pubmed.ncbi.nlm.nih.gov/33514739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33514739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33514739", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Net39 knockout causes muscle nuclear defects, altered chromatin/transcription and lethal myopathy.", "what_it_does_not_show": "Severe structural failure/global illness and a membrane tether distinct from lamin filaments limit direct transcription-specific inference.", "confounders_present": [ "Severe structural failure/global illness and a membrane tether distinct from lamin filaments limit direct transcription-specific inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 54, "pmid": "28049722", "title": "The LINC complex contributes to heterochromatin organisation and transcriptional gene silencing in plants.", "citation": "Poulet A, Duc C, Voisin M et al. The LINC complex contributes to heterochromatin organisation and transcriptional gene silencing in plants. Journal of cell science. 2017.", "doi": "10.1242/jcs.194712", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28049722/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28049722/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28049722", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "plant in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Plant LINC mutants alter peripheral heterochromatin position/compaction and repeat silencing.", "what_it_does_not_show": "Plants lack canonical metazoan lamin filaments; evidence supports an envelope architecture principle, not mammalian lamin-specific necessity.", "confounders_present": [ "Plants lack canonical metazoan lamin filaments; evidence supports an envelope architecture principle, not mammalian lamin-specific necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 55, "pmid": "24700158", "title": "Unique and shared functions of nuclear lamina LEM domain proteins in Drosophila.", "citation": "Barton LJ, Wilmington SR, Martin MJ et al. Unique and shared functions of nuclear lamina LEM domain proteins in Drosophila. Genetics. 2014.", "doi": "10.1534/genetics.114.162941", "pmcid": "PMC4063922", "url": "https://pubmed.ncbi.nlm.nih.gov/24700158/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24700158/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24700158", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Drosophila LEM proteins show redundant viability effects but different tissue-specific defects and rescue capacities.", "what_it_does_not_show": "Broad essentiality and ectopic rescue distinguish network redundancy, not all-domain transcriptional repression.", "confounders_present": [ "Broad essentiality and ectopic rescue distinguish network redundancy, not all-domain transcriptional repression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 56, "pmid": "27099177", "title": "Laminopathies disrupt epigenomic developmental programs and cell fate.", "citation": "Perovanovic J, Dell'Orso S, Gnochi VF et al. Laminopathies disrupt epigenomic developmental programs and cell fate. Science translational medicine. 2016.", "doi": "10.1126/scitranslmed.aad4991", "pmcid": "PMC4939618", "url": "https://pubmed.ncbi.nlm.nih.gov/27099177/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27099177/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27099177", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "disease cellular and animal tissue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LMNA-mutant DamID and patient samples show altered developmental LAD transitions and persistent Sox2; Sox2 overexpression impairs differentiation.", "what_it_does_not_show": "Mutant fusion and overexpression plus patient associations do not selectively test lamin tethering versus other nuclear functions.", "confounders_present": [ "Mutant fusion and overexpression plus patient associations do not selectively test lamin tethering versus other nuclear functions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 57, "pmid": "42106913", "title": "Effects of chromatin-lamina attachment on extra-long-range chromatin interactions.", "citation": "Delafrouz P, Farooq H, Du L et al. Effects of chromatin-lamina attachment on extra-long-range chromatin interactions. Biophysical journal. 2026.", "doi": "10.1016/j.bpj.2026.05.011", "pmcid": "PMC13241299", "url": "https://pubmed.ncbi.nlm.nih.gov/42106913/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42106913/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID40027763" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42106913", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "computational model with primary data integration", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Polymer models incorporating LAD maps reproduce radial distributions and predict extra-long contacts.", "what_it_does_not_show": "Simulated tethering is not an endogenous perturbation or independent functional transcription test; earlier preprint excluded.", "confounders_present": [ "Simulated tethering is not an endogenous perturbation or independent functional transcription test; earlier preprint excluded." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 58, "pmid": "40440430", "title": "Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation.", "citation": "Labade AS, Chiang ZD, Comenho C et al. Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation. Science (New York, N.Y.). 2025.", "doi": "10.1126/science.adt2781", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40440430/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40440430/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39386718" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40440430", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational cellular", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ExIGS relates local lamin abnormalities in progeria cells to chromatin/transcriptional hotspots.", "what_it_does_not_show": "Spatial association and a disease background do not establish causal direction or broad repression; preprint excluded.", "confounders_present": [ "Spatial association and a disease background do not establish causal direction or broad repression; preprint excluded." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 59, "pmid": "38719473", "title": "Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription.", "citation": "Keenan CR, Coughlan HD, Iannarella N et al. Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription. Genome research. 2024.", "doi": "10.1101/gr.279119.124", "pmcid": "PMC11146594", "url": "https://pubmed.ncbi.nlm.nih.gov/38719473/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38719473/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38719473", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "endogenous cellular", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Suv39 double-knockout reduces expression of peripheral euchromatic genes with changed 3D organization, despite heterochromatin-loss expectation.", "what_it_does_not_show": "Histone-enzyme loss affects compaction and topology; functional direction is not simple repression release, and lamina mediation is inferred rather than selectively rescued.", "confounders_present": [ "Histone-enzyme loss affects compaction and topology; functional direction is not simple repression release, and lamina mediation is inferred rather than selectively rescued." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 60, "pmid": "41909953", "title": "B-type lamins maintain transcriptional homeostasis by spatially controlling chromatin-speckle proximity.", "citation": "Shin GS, Kim J, Kim JY et al. B-type lamins maintain transcriptional homeostasis by spatially controlling chromatin-speckle proximity. Nucleic acids research. 2026.", "doi": "10.1093/nar/gkag283", "pmcid": "PMC13034045", "url": "https://pubmed.ncbi.nlm.nih.gov/41909953/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41909953/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41909953", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph1, 2:Results:paragraph0, 2:Results:paragraph5, 2:Results:paragraph31, 2:Results:paragraph32. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "endogenous human cellular", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Original H1299B-lamin CRISPR knockouts reduce nascent RNA and correlate non-LAD speckle-distance shifts with RNA changes, alongside higher apoptosis and lower proliferation.", "what_it_does_not_show": "Chronic whole-protein loss, cell death and correlations do not isolate a speckle-distance mediator; this is not an acute endogenous degron or selective silencer-recruitment test.", "confounders_present": [ "Chronic whole-protein loss, cell death and correlations do not isolate a speckle-distance mediator; this is not an acute endogenous degron or selective silencer-recruitment test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "H1299 tumor-cell knockout/clonal assays; RNA and distance measurements share whole-protein perturbation and apoptosis/proliferation failure modes." ] } ], "verification_summary": { "load_bearing_claims_checked": 65, "verified": 65, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "LAD genes have lower average expression across organism and cell-state maps, with active escapers and dynamic intermediate peripheral domains. This descriptive existence claim remains Β; lamina contact does not itself identify a causal silencer.", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "The nuclear lamina globally regulates gene expression by tethering and silencing lamina-associated domains, rather than serving a primarily mechanical role.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Intact-cell endogenous perturbations are judged under rubric03, with specificity and functional native transcription required. Pure LAD mapping remains Β. Synthetic peripheral tethering and reporter integrations test their construct/promoter contexts and cannot establish global native necessity; biochemical interaction and polymer simulation remain partial support. Local positive lamin/HDAC perturbations are retained, but whole-enzyme loss is not selective proof of lamina recruitment. SC4 is limited by a missing positive selective full-scope test and actual contrary controls, not by wrongly applying a reporter-only cap to every endogenous experiment.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Imaging, contact enrichment, histone co-occurrence and reporter behavior alone do not cross the native functional boundary.", "SC2 contains endogenous functional perturbations, topology rescue and actual context controls; not just FRAP or contact enrichment.", "SC3 lacks selective recruitment disruption/rescue even where the silencing enzyme itself matters.", "SC4 includes native contrary/null tests and global secondary effects; no isolated all-state direct repressive mechanism crosses its boundary." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "LAD genes have lower average expression across organism and cell-state maps, with active escapers and dynamic intermediate peripheral domains. This descriptive existence claim remains Β; lamina contact does not itself identify a causal silencer.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID30201095, PMID30862957, PMID29529026, PMID36333314, PMID31988151", "gamma_hard_rules_triggered": [ "Imaging, contact enrichment, histone co-occurrence and reporter behavior alone do not cross the native functional boundary.", "SC2 contains endogenous functional perturbations, topology rescue and actual context controls; not just FRAP or contact enrichment.", "SC3 lacks selective recruitment disruption/rescue even where the silencing enzyme itself matters.", "SC4 includes native contrary/null tests and global secondary effects; no isolated all-state direct repressive mechanism crosses its boundary." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Endogenous lamin loss/restoration changes topology and functional gene regulation in defined contexts. Matched cell-cycle TKO/B1-rescue experiments, specific Drosophila loci, heat-shock responses and Gata4-dependent lineage rescue support a genuine contribution, with stem-state, isoform and mechanical boundaries. Whole-protein loss does not isolate every topology/speckle mediator.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Imaging, contact enrichment, histone co-occurrence and reporter behavior alone do not cross the native functional boundary.", "SC2 contains endogenous functional perturbations, topology rescue and actual context controls; not just FRAP or contact enrichment.", "SC3 lacks selective recruitment disruption/rescue even where the silencing enzyme itself matters.", "SC4 includes native contrary/null tests and global secondary effects; no isolated all-state direct repressive mechanism crosses its boundary." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Local HDAC/SIRT7 and lamin-dependent effects provide mechanistic support, but enzyme activity required for repression is not the same as necessity of recruitment by lamin. HDAC1 silencing can change without detachment, HDAC3 detachment can change without silencing, and native/reporter screens implicate chromatin regulators with weak/variable NL dependence. Selective recruitment-defective loss/rescue at native LADs remains unverified.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Imaging, contact enrichment, histone co-occurrence and reporter behavior alone do not cross the native functional boundary.", "SC2 contains endogenous functional perturbations, topology rescue and actual context controls; not just FRAP or contact enrichment.", "SC3 lacks selective recruitment disruption/rescue even where the silencing enzyme itself matters.", "SC4 includes native contrary/null tests and global secondary effects; no isolated all-state direct repressive mechanism crosses its boundary." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The global direct-tethering/silencing claim is not supported by lamina association alone and is challenged by lamin-null stem-cell competence, lack of preferential LAD derepression, transcriptionally competent peripheral loci and short-term detachment with minor expression effects. Contextual gene regulation is real; constitutive all-state enzymatic repression rather than mechanics/network effects has not been isolated.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Use endogenous contact/tether manipulation with native transcription, matched local chromatin and cell-cycle controls before assigning a mechanistic direction to LAD maps." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "yes", "supporting_evidence": [ "[17] Lamin TKO changes selected LAD/topological interactions and B1 restoration partly reverses topology with matched cell-cycle profiles.", "[21] Drosophila NL disruption changes LAD compaction/acetylation/background expression and global contacts.", "[22] AGO2 null versus catalytic mutation and laminB depletion distinguish topology-linked regulation at an endogenous Drosophila locus.", "[23] Lmna loss alters naive stem-cell cardiac fate and architecture, with Gata4 reduction/allele rescue; effects reverse in progenitors/cardiomyocytes and differ from B1 loss.", "[25] LaminA/C and nuclear myosin are required for heat-shock Hsp70 locus repositioning, speckle organization and induction." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with clear scope restriction. Many enhancer, condensate, or accessibility claims belong here.", "satisfied": "yes", "supporting_evidence": [ "[17] Lamin TKO changes selected LAD/topological interactions and B1 restoration partly reverses topology with matched cell-cycle profiles.", "[21] Drosophila NL disruption changes LAD compaction/acetylation/background expression and global contacts.", "[22] AGO2 null versus catalytic mutation and laminB depletion distinguish topology-linked regulation at an endogenous Drosophila locus.", "[23] Lmna loss alters naive stem-cell cardiac fate and architecture, with Gata4 reduction/allele rescue; effects reverse in progenitors/cardiomyocytes and differ from B1 loss.", "[25] LaminA/C and nuclear myosin are required for heat-shock Hsp70 locus repositioning, speckle organization and induction." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal tests across loci or systems\n- Specificity beyond global transcriptional collapse\n- Narrowing of key alternatives", "satisfied": "no", "supporting_evidence": [ "[17] Lamin TKO changes selected LAD/topological interactions and B1 restoration partly reverses topology with matched cell-cycle profiles.", "[21] Drosophila NL disruption changes LAD compaction/acetylation/background expression and global contacts.", "[22] AGO2 null versus catalytic mutation and laminB depletion distinguish topology-linked regulation at an endogenous Drosophila locus.", "[23] Lmna loss alters naive stem-cell cardiac fate and architecture, with Gata4 reduction/allele rescue; effects reverse in progenitors/cardiomyocytes and differ from B1 loss.", "[25] LaminA/C and nuclear myosin are required for heat-shock Hsp70 locus repositioning, speckle organization and induction." ], "what_would_cross_it": "Combine rapid endogenous depletion with expression-matched topology-versus-mechanics separation alleles and mediator rescue; reproduce native transcription effects across predefined cell states without global collapse." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Disrupt only the endogenous lamin-silencer interaction while preserving lamina structure, enzyme levels and catalytic competence; prove recruitment loss changes native LAD transcription and recruitment-specific rescue restores repression." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Show a preregistered cross-state native transcription prediction from selective lamina-tether/silencer disruption, with matched mechanical rescue, viable cell-cycle profiles and redundant-tether controls. Explain retained gene output after short-term detachment and the opposing activation effects." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Lamin-null ESC/TE transcription changes do not correlate with lamin-bound promoters (22116031).", "Essentially all-lamin loss preserves genome-wide emerin contacts in mESCs (25784758).", "TKO detached LAD genes are not preferentially derepressed; B1 re-expression partly rescues topology with additional ectopic contacts (30201095).", "Drosophila HDAC1 affects silencing without contact loss, while HDAC3 affects positioning without comparable repression (23226217).", "LMNB1 is a modest reporter-screen hit in LAD5 but not LAD6; matching expression reduces apparent NELF LAD specificity (39322756).", "LBR/LAP2-related short-term detachment changes few genes and additional B-type-lamin depletion does not enhance tether loss (41735607).", "A-type-lamin effects differ by naive stem/progenitor/cardiomyocyte state, and B1 loss does not reproduce the same cardiac fate effect (36333314)." ], "note": "Measured boundaries are native locus/promoter, lamin isoform, redundant tether complement, differentiation state, species, stress condition and depletion duration. Cell-cycle/viability and whole-protein secondary effects remain explicit. Active peripheral genes and null contexts are retained, not retrospectively removed as irrelevant." }, "falsification_patterns_met": [ { "pattern": "Global immediate filament-driven repression prediction challenged by native nulls", "evidence": "Lamin-null competence, lack of detached-LAD gene derepression and minor72hourRNAeffects after tether loss undermine the full-scope prediction. The uncrossed global boundary and restrictedΓ already incorporate this failure; no duplicate numerical downgrade is applied.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "LAD binding treated as repression necessity", "where": "Contact maps do not determine causal direction." }, { "pitfall": "Whole lamin loss treated as selective silencer loss", "where": "Mechanics, replication stress, motors and differentiation can mediate RNA changes." }, { "pitfall": "Reporter position generalized to native chromatin", "where": "Synthetic tethering and multicopy arrays have distinct promoters and activation strengths." }, { "pitfall": "Chromatin and nuclear envelope collapsed into one mechanism", "where": "LBR/LAP2/LEM redundancy and H3K9 compaction can remain without lamins." }, { "pitfall": "Multiple assays counted as independent causal studies", "where": "Topology and RNA measurements often share the same knockout clones." } ], "causal_tally_audit": { "tally_claimed_by_document": 3, "tally_after_audit": 3, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 49, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Reports sharing participants, models or instruments are not independent causal lines.", "Pivotal nulls do not earn positive threshold crossings." ] }, "steelman": { "case_one_rung_higher": "One rung above, Δ: lamin loss changes topology, native transcription and differentiation, and rescue experiments preserve a real regulatory function. The2025human multi-lamin study strengthens the argument by linking SON interaction to organizational and RNA rescue. But SC4 is direct global tethering/enzymatic repression across states, not any RNA response to protein loss. Cell-state reversals, preserved repression after detachment and redundant tethers leave that selective full-scope causal test uncrossed.", "case_one_rung_lower": "One rung below, Β: much of the global narrative rests on LAD maps and expression anticorrelation. Yet local lamin/HDAC, native locus and genetic rescue experiments provide genuine mechanistic support beyond association. Γ preserves those partial-system results without pretending they establish global silencer recruitment.", "which_rejected": "Retain globalΓ and narrowSC2Ε. A causal architecture effect is not erased by native silencing exceptions, while whole-protein rescue does not by itself identify direct enzymatic repression. The proposed selective interaction experiment is the named blocker.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Engineer an endogenous lamin allele that loses a specified silencer interaction while preserving filament mechanics, envelope integrity and redundant-tether localization. Compare it with a mechanical-defect allele and expression-matched rescue across predefined stem and differentiated states. Perform short-time-course native nascent RNA plus contact/speckle mapping, with cell-cycle, replication stress and viability controls. Re-tether the enzyme selectively at native affected loci to test whether repression is restored before downstream damage." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Moderate reflects evidence density and reproducibility, not access depth. Sixty primary reports span many laboratories, species and assay modalities, but on the registered global question the results are heterogeneous and partly opposed: whole-lamin loss changes expression bidirectionally, lamin-null embryonic stem cells self-renew with no relation between lamin-bound promoters and RNA change, short detachment gives minor RNA effects while chronic detachment gives large ones confounded by stress, death and proliferation loss, and redundant envelope tethers are not separated from filament mechanics. Those are substantive reproducibility and confounding reservations, not gaps in reading access.", "rests_on_non_peer_reviewed_work": false, "rationale": "Scope-matched aggregation is fixed to global SC4 and yields Γ. SC2 has mapped context-specific Ε support, while SC1 remains Β and direct enzyme-recruitment necessity SC3 remains Γ. Whole-lamin deletion can change thousands of genes yet still fail to establish direct global repression: changes can be bidirectional, follow mechanics/stress, or depend on other envelope tethers. This is not a judgment that lamins lack regulatory function." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Native genetic and NET perturbations exclude an epiphenomenal-only role in specific contexts. But global repression can persist without lamin filaments or after major detachment, and no universal necessity, initiating sufficiency and rate limitation are jointly demonstrated. Lamins stabilize architecture, responses and some lineage programmes within an envelope/chromatin network; step5 best describes that contextual contribution.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The2025human lamin/SON knockout-rescue study (41205174),2026LBR/LAP2 deconvolution (41735607),2024LAD genetic screens (39322756) and2026lamin-isoform LBR experiments (42153377) actively test mechanisms and redundancy; none completes a selective global silencer-recruitment proof. The2026B-lamin/speckle original (41909953) supplies actual RNA and positional tests with explicit death/proliferation limits.", "justification": "The2025human lamin/SON knockout-rescue study (41205174),2026LBR/LAP2 deconvolution (41735607),2024LAD genetic screens (39322756) and2026lamin-isoform LBR experiments (42153377) actively test mechanisms and redundancy; none completes a selective global silencer-recruitment proof. The2026B-lamin/speckle original (41909953) supplies actual RNA and positional tests with explicit death/proliferation limits." }, "stability": { "value": "Stable", "trigger": "No verified named pending result was identified that demonstrably determines the full-scope letter; this is a bounded search finding, not proof that none exists.", "justification": "No verified named pending result was identified that demonstrably determines the full-scope letter; this is a bounded search finding, not proof that none exists." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Engineer an endogenous lamin allele that loses a specified silencer interaction while preserving filament mechanics, envelope integrity and redundant-tether localization. Compare it with a mechanical-defect allele and expression-matched rescue across predefined stem and differentiated states. Perform short-time-course native nascent RNA plus contact/speckle mapping, with cell-cycle, replication stress and viability controls. Re-tether the enzyme selectively at native affected loci to test whether repression is restored before downstream damage.", "readout": "Native nascent transcription, locus contact/topology and speckle distance, independent mechanics and nuclear-integrity measurements", "critical_control": "Endogenous protein levels, enzyme catalytic competence, tether complement, mechanical rescue, cell state/time, cell cycle, replication stress, viability and expression-matched rescue", "supporting_result": "Selective recruitment loss derepresses prespecified native LAD outputs across states, with interaction/locus-specific rescue and no mechanical or global-collapse explanation", "falsifying_result": "Tether/recruitment loss leaves repression intact or changes RNA only after mechanics, stress, differentiation or global transcription collapse" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Separate necessity of a silencing enzyme from necessity of its recruitment by lamin.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Quantify native transcription after rapid detachment before chronic epigenetic/stress amplification.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Dissect B-type versus A-type lamin functions and LBR/LAP2/LEM/PRR14 redundancy by cell state.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Test whether speckle distance mediates RNA changes rather than being a correlated consequence of global disorganization.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Separate mechanical and chromatin-tether rescue with endogenous matched alleles.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Retain active LAD promoters and opposing differentiation effects in global prediction tests.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-12", "reviewer": "Codex", "evidence_base_note": "60 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite is queried per case where connected; received tallies/outgoing reference contexts are not audited incoming contrasting statements. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": true, "why_not_sufficient": "Endogenous knockout/rescue, locus-specific NET manipulations, disease alleles, graded lamin levels and temporal depletion were considered as field-valid equivalents. Narrow contexts support Ε, while native readouts, rescue specificity and error-mode independence would be needed for Ζ. The global nominal cannot advance on artificial reporter sufficiency or correlation between gene and topology changes;2025human triple-loss/speckle rescue is a strong lead but abstract-only access and global transcription/homeostasis changes leave mediator specificity unresolved. No requirement for a human clinical RCT is imposed on a cellular mechanism." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Endogenous knockout/rescue, locus-specific NET manipulations, disease alleles, graded lamin levels and temporal depletion were considered as field-valid equivalents. Narrow contexts support Ε, while native readouts, rescue specificity and error-mode independence would be needed for Ζ. The global nominal cannot advance on artificial reporter sufficiency or correlation between gene and topology changes;2025human triple-loss/speckle rescue is a strong lead but abstract-only access and global transcription/homeostasis changes leave mediator specificity unresolved. No requirement for a human clinical RCT is imposed on a cellular mechanism." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous knockout/rescue, locus-specific NET manipulations, disease alleles, graded lamin levels and temporal depletion were considered as field-valid equivalents. Narrow contexts support Ε, while native readouts, rescue specificity and error-mode independence would be needed for Ζ. The global nominal cannot advance on artificial reporter sufficiency or correlation between gene and topology changes;2025human triple-loss/speckle rescue is a strong lead but abstract-only access and global transcription/homeostasis changes leave mediator specificity unresolved. No requirement for a human clinical RCT is imposed on a cellular mechanism." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous knockout/rescue, locus-specific NET manipulations, disease alleles, graded lamin levels and temporal depletion were considered as field-valid equivalents. Narrow contexts support Ε, while native readouts, rescue specificity and error-mode independence would be needed for Ζ. The global nominal cannot advance on artificial reporter sufficiency or correlation between gene and topology changes;2025human triple-loss/speckle rescue is a strong lead but abstract-only access and global transcription/homeostasis changes leave mediator specificity unresolved. No requirement for a human clinical RCT is imposed on a cellular mechanism." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous knockout/rescue, locus-specific NET manipulations, disease alleles, graded lamin levels and temporal depletion were considered as field-valid equivalents. Narrow contexts support Ε, while native readouts, rescue specificity and error-mode independence would be needed for Ζ. The global nominal cannot advance on artificial reporter sufficiency or correlation between gene and topology changes;2025human triple-loss/speckle rescue is a strong lead but abstract-only access and global transcription/homeostasis changes leave mediator specificity unresolved. No requirement for a human clinical RCT is imposed on a cellular mechanism." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 65, "claims_verified": 65, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Drosophila lamin-contact genes are silent, late-replicating and depleted of active marks; activation reduces binding. Genome mapping and activation-linked movement do not identify which direction causes repression.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "Human fibroblast maps identify large LADs with low expression and sharp domain boundaries. Association is not necessary enzymatic repression; linked erratum lacks identifier/details in examined metadata.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "Single-cell human maps show variable and stable LAD contacts inversely linked to gene activity. Contact consistency and histone correlation do not selectively manipulate lamins or demonstrate transcriptional necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Twelve-cell-type atlas identifies deep and intermediate peripheral chromatin with different expression/accessibility. Atlas broadens descriptive scope, not causal scope; proximity to lamina differs from direct contact.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "Single-cell LAD contacts are intermittent, reshuffled after mitosis and regulated by G9a. H3K9 methylation may regulate anchoring; contact-memory assay does not establish lamina recruitment as the obligatory source of silencing.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "Inducible INM tethering can reposition and repress selected chromosomal regions after mitosis. Ectopic targeting tests sufficiency of the construct/context, not necessity of endogenous lamin-mediated repression genome-wide.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Lamin-B1-tethered peripheral transgene array retains inducible transcription and similar induction kinetics. Large multicopy synthetic array and strong Tet activation are not every native promoter; peripheral positioning is not universally sufficient to silence.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph17, 1:Results:paragraph20. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "Promoters moved from LADs and reporters inserted across chromatin show promoter/local-context-dependent repression and escapers. Relocation/reporter designs establish contextual sufficiency, not lamina filament or recruited-enzyme necessity for all native LAD genes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "LAD reporter screens identify many chromatin regulators and few envelope hits; LMNB1 is modest in one LAD and null in another; native-gene CRISPRi tests NELF. Essential proteins and redundancy may be missed; matched-expression analysis reduces apparent LAD preference. Native NELF effect does not prove its recruitment by lamina.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph14, 1:Results:paragraph22, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "Drosophila lamin and HDAC knockdowns identify local chromatin/transcription effects; HDAC1 silences while HDAC3 contributes anchoring. HDAC1 acts beyond tightly bound genes and changes growth modestly; selective lamina-HDAC interaction loss/rescue is absent. Local support is not global enzyme necessity.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results and Discussion:paragraph0, 2:Results and Discussion:paragraph2, 2:Results and Discussion:paragraph4, 2:Results and Discussion:paragraph6, 2:Results and Discussion:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "Active in-LAD genes contact enhancers; A-type but not B1 lamins contribute to repression near one active-region border. Limited loci and differentiation state; not every LAD is silent or regulated identically, and contact alone is not enhancer causality.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "Muscle-specific NET depletion/repositioning changes selected developmental-gene repression and myogenesis. NETs rather than lamin filaments are targeted; combined loss affects differentiation. Tissue-specific architecture does not establish a global lamin mechanism.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "Peripheral H3K9me2-only enhancer domains have limited LaminB interaction and differ from LADs. Poised enhancer mapping is descriptive; nuclear periphery cannot be treated as synonymous with lamin contact or complete inactivity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "Peripheral relocation advances heterochromatin replication and impairs silencing-mark maintenance. Synthetic repositioning and replication endpoints do not prove endogenous transcriptional output; it opposes uniform repressive direction.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "B-lamin-null ESCs retain self-renewal and differentiation; expression changes do not correlate with lamin-bound promoters, while organogenesis requires lamins. Mouse ESC/TE contexts differ from tissues and chronic compensation is possible; lamin absence is not absence of all envelope tethers.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Main text:paragraph3, 1:Main text:paragraph4, 1:Main text:paragraph9. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "Essentially all-lamin removal leaves genome-wide emerin-contact organization detectable in mouse ESCs. Emerin marks envelope contact, not every mesoscale interaction or functional output; redundancy and cell state remain.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Lamin TKO changes selected LAD/topological interactions and B1 restoration partly reverses topology with matched cell-cycle profiles. Detached LAD genes are not preferentially upregulated; RNA changes correlate with altered interactions but selective topology-to-transcription mediation is incomplete. Re-expression also creates non-native interactions.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph4, 1:Results:paragraph15, 1:Results:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "Human lamin KO maps state-dependent genome/speckle disorganization and lower transcription; WT-A versus SON-binding-defective mutant rescue differs. Whole-protein chronic loss and reduced global transcription/homeostasis limit specificity; original abstract only, not audited Methods or matched-rescue levels.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "LaminB1 decline accompanies neuronal locus movement and ectopic B1 blocks movement/Egr3 expression. Overexpression demonstrates a construct effect, not endogenous-B1 necessity or global silencing; maturation is a concurrent change.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "LaminA/emerin depletion changes actin/NM1, chromatin mobility, locus positioning and selected expression; motor/actin interventions restore mobility. Cytoskeletal alterations provide an alternative mediator; mobility rescue is not necessarily transcriptional rescue or direct lamina silencing.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "Drosophila NL disruption changes LAD compaction/acetylation/background expression and global contacts. Chronic RNAi and polymer simulations do not isolate a unique enzymatic silencing route; organism/cell context restricts inference.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "AGO2 null versus catalytic mutation and laminB depletion distinguish topology-linked regulation at an endogenous Drosophila locus. AGO2 has multiple nuclear functions; endogenous local regulation is not proof of lamina-recruited enzyme necessity genome-wide.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "Lmna loss alters naive stem-cell cardiac fate and architecture, with Gata4 reduction/allele rescue; effects reverse in progenitors/cardiomyocytes and differ from B1 loss. Mechanistic narrowing identifies a TF-mediated context, but no selective tethering-versus-mechanics allele proves global LAD enzymatic repression. Disease point mutations differ from null.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph27, 1:Results:paragraph41, 1:Results:paragraph43. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "Interior phospho-laminA/C binds active enhancers rather than LADs, with altered enhancer/expression patterns in progeria. Binding and disease association do not demonstrate direct enhancer causality; intranuclear lamins are distinct from peripheral tethering.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "LaminA/C and nuclear myosin are required for heat-shock Hsp70 locus repositioning, speckle organization and induction. Inducible activation rather than repression; motor, stress and structure effects are intertwined and locus-specific.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "LBR and laminA/C sequentially/redundantly tether heterochromatin; combined absence inverts architecture and tether losses have opposite myoblast expression effects. Redundant cell-specific NE network rather than one universal lamin repression pathway; topology inversion is not necessarily transcriptional loss.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "LBR/LAP2 redundancy maintains peripheral heterochromatin; short-term detachment changes expression little, prolonged knockout changes expression/marks and cell fate. Additional B-lamin depletion does not enhance defined tether-loss phenotype; long-term stress/TF amplification and mixed direction prevent direct enzymatic causality at all LADs.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph12, 1:Results:paragraph19, 1:Results:paragraph23, 1:Results:paragraph32. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "Lamin isoform re-expression in null fibroblasts differentially alters LBR anchorage and mobility. Ectopic expression and phosphorylation effects define architecture, not a transcriptional endpoint or universal direct gene repression; preprint not counted separately.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "LEMD2 localization depends on laminA/C but LEMD2 alone or with laminC fails to restore peripheral heterochromatin in rods. Negative synthetic rescue tests one candidate network component; does not exclude other redundant tethers or all roles for lamins.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "PRR14 links HP1-marked chromatin and lamina with ordered mitotic reassembly. Anchoring/localization function is not demonstrated necessary global transcriptional silencing.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "PRR14 domain dissection separates chromatin and lamina binding with phosphorylation regulation. Construct localization sufficiency and dynamics do not prove natural gene-output dependence.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "PRR14/HP1 interactions dynamically organize H3K9me3 chromatin at lamina independent of mitosis. Imaging and HP1 domain manipulation define tether biology; endogenous transcriptional mediation remains untested in the examined abstract.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "CEC4 is necessary for endogenous worm heterochromatin anchoring but not transcriptional repression, while affecting induced cell-fate commitment. CEC4 localizes independently of nuclear lamin; ectopic muscle induction is a restricted cell-fate test, not global natural differentiation necessity.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "MRG1/CEC4 and CBP1/ATF8 epistasis separates active-chromatin retention from direct peripheral anchoring in worms. Distinct embryonic/differentiated contexts and broad acetylation changes; this is not a lamina-recruited silencer mechanism.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "H3K9 methyltransferase and CEC4 mutants impair compartments through separable compaction and anchoring mechanisms with little expression change. Gene expression remains largely intact despite compartment switching; heterochromatin self-association and anchoring cannot be equated with lamin-global repression.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "CEC4 ablation rescues lamin-mutant worm positioning, some transcription and muscle function. Mutant forced disease model scope is restricted; relieving attachment helps, opposing a uniform more-tethering-equals-healthier-repression model.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "CEC4-mediated anchoring contributes to nuclear migration/deformability in LINC-defective worms and lamin-stabilizing mutation rescues. Mechanical phenotype, conditional LINC background and gene-output absence; anchoring has a mechanical role rather than proof of global transcriptional primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "LINC/lamin depletion alters early nucleolar timing, with CEC4 epistasis and heterochromatin spatial changes. Embryonic assembly phenotype differs from LAD transcription; nuclear-envelope perturbations have multiple structural/cell-cycle functions.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "Lmna-null fibroblasts show impaired mechanical resistance, survival under strain and mechanically activated NFkB transcription. Functional mechanics is a real lamin contribution; viability and cytoskeletal signaling must be separated from direct LAD repression.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "LaminA levels track tissue stiffness and graded manipulation modifies matrix-directed differentiation and receptor trafficking. Stiffness-response feedback and level manipulation are not direct enzymatic repression or complete separation of mechanics from regulation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "Lamin mutants alter actin/MKL1-SRF signaling and emerin expression restores trafficking and actin dynamics. Ectopic rescue and mechanical/nuclear-actin mediation do not establish peripheral chromatin recruitment as the cause.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "LaminA/C knockdown leaves vibration-induced adipogenesis repression and focal-adhesion activation intact despite nuclear mechanical changes. Specific mechanical protocol and partial depletion restrict generalization; not every mechanotransduction response requires A-type lamin.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "LaminA/C-deficient human myotubes show amplified stretch-related deformation, accessibility and transcriptional stress responses. Mechanical challenge and damage responses are inseparable in this design; ATAC/marks alone would not establish regulation, while accompanying RNA still lacks direct tether specificity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "Adult cardiomyocyte Lmna deletion triggers perinuclear stress before cardiac dysfunction; stress/autophagy drugs delay disease. Therapeutic benefit identifies a downstream stress pathway, not universal LAD repression; mutant disease model and pleiotropic drugs remain.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "Two prelamin/progeria models show ATM/NEMO/NFkB inflammation, with genetic/pharmacologic blockade improving disease and survival. Accelerated-aging genetic models do not establish ordinary global gene silencing; damage-signaling mechanism competes with direct repression.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "MOF/NSL loss alters lamin acetylation and nuclear stability; HDAC inhibition or acetylation mimic rescues abnormal architecture. Broad chromatin/architecture effects and ectopic rescue; transcription loss in nuclear abnormalities may reflect global damage. Linked2019correction details not audited.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "SIRT7 depletion increases L1 expression/retrotransposition and H3K18 acetylation with impaired lamin association. L1 repeat subset and enzyme-to-anchoring direction; selective recruitment-defective interaction rescue is needed to establish lamina-dependent repression rather than parallel effects.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "LaminA deficiency destabilizes speckle METTL3/14 reservoir and METTL14 overexpression reduces senescence markers. RNA methylation reservoir and senescence models are not direct LAD silencing or organismal healthspan; overexpression/markers retain caps.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "Lmna-null heart transcriptome alterations precede dysfunction and AAV-lamin rescue restores many genes with improved function/survival. Whole-protein rescue restores mechanics and transcription together; upstream regulator inference does not demonstrate direct peripheral silencer recruitment.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "LMNA-CMD mutations impair strain/YAP response and muscle growth with functional overload; related EDMD models differ. Disease allele/lineage and mechanics specificity map context, not a global transcriptionally repressive lamina role.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "Lmna loss suppresses stimulated microglial proliferation/activation with proteomic and immune changes. Proliferation and response-state differences may mediate RNA/protein output; mechanotransduction is proposed, not selectively proved.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "T-cell Lmna loss shifts Treg/Th1 differentiation and lessens adoptive-transfer colitis with TF chromatin changes. Forced recipient model tests transferred cells, not spontaneous disease; lineage and RA environment matter and no global LAD mechanism is isolated.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "Net39 knockout causes muscle nuclear defects, altered chromatin/transcription and lethal myopathy. Severe structural failure/global illness and a membrane tether distinct from lamin filaments limit direct transcription-specific inference.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C54", "text": "Plant LINC mutants alter peripheral heterochromatin position/compaction and repeat silencing. Plants lack canonical metazoan lamin filaments; evidence supports an envelope architecture principle, not mammalian lamin-specific necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C55", "text": "Drosophila LEM proteins show redundant viability effects but different tissue-specific defects and rescue capacities. Broad essentiality and ectopic rescue distinguish network redundancy, not all-domain transcriptional repression.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C56", "text": "LMNA-mutant DamID and patient samples show altered developmental LAD transitions and persistent Sox2; Sox2 overexpression impairs differentiation. Mutant fusion and overexpression plus patient associations do not selectively test lamin tethering versus other nuclear functions.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C57", "text": "Polymer models incorporating LAD maps reproduce radial distributions and predict extra-long contacts. Simulated tethering is not an endogenous perturbation or independent functional transcription test; earlier preprint excluded.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C58", "text": "ExIGS relates local lamin abnormalities in progeria cells to chromatin/transcriptional hotspots. Spatial association and a disease background do not establish causal direction or broad repression; preprint excluded.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C59", "text": "Suv39 double-knockout reduces expression of peripheral euchromatic genes with changed 3D organization, despite heterochromatin-loss expectation. Histone-enzyme loss affects compaction and topology; functional direction is not simple repression release, and lamina mediation is inferred rather than selectively rescued.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C60", "text": "Original H1299B-lamin CRISPR knockouts reduce nascent RNA and correlate non-LAD speckle-distance shifts with RNA changes, alongside higher apoptosis and lower proliferation. Chronic whole-protein loss, cell death and correlations do not isolate a speckle-distance mediator; this is not an acute endogenous degron or selective silencer-recruitment test.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph1, 2:Results:paragraph0, 2:Results:paragraph5, 2:Results:paragraph31, 2:Results:paragraph32. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "LAD genes have lower average expression across organism and cell-state maps, with active escapers and dynamic intermediate peripheral domains. This descriptive existence claim remains Β; lamina contact does not itself identify a causal silencer.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 8, 11, 13, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "Endogenous lamin loss/restoration changes topology and functional gene regulation in defined contexts. Matched cell-cycle TKO/B1-rescue experiments, specific Drosophila loci, heat-shock responses and Gata4-dependent lineage rescue support a genuine contribution, with stem-state, isoform and mechanical boundaries. Whole-protein loss does not isolate every topology/speckle mediator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5, 6, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "Local HDAC/SIRT7 and lamin-dependent effects provide mechanistic support, but enzyme activity required for repression is not the same as necessity of recruitment by lamin. HDAC1 silencing can change without detachment, HDAC3 detachment can change without silencing, and native/reporter screens implicate chromatin regulators with weak/variable NL dependence. Selective recruitment-defective loss/rescue at native LADs remains unverified.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 43, 46, 47, 54, 56, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC4", "text": "The global direct-tethering/silencing claim is not supported by lamina association alone and is challenged by lamin-null stem-cell competence, lack of preferential LAD derepression, transcriptionally competent peripheral loci and short-term detachment with minor expression effects. Contextual gene regulation is real; constitutive all-state enzymatic repression rather than mechanics/network effects has not been isolated.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 3, 4, 6, 7, 8, 9, 13, 14, 15, 16, 17, 18, 20, 23, 24, 26, 27, 33, 35, 37, 39, 40, 41, 42, 43, 44, 45, 48, 49, 50, 51, 52, 53, 55, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "Lamins help organize genomes and regulate genes in defined settings; peripheral contact is not a universal gene-off switch, and global lamina-driven enzymatic silencing remains unestablished.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 15, 17, 9, 23, 27, 10 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Pickersgill H, Kalverda B, de Wit E et al. Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nature genetics. 2006.", "tier": "A", "kind": "primary", "pmid": "16878134", "doi": "10.1038/ng1852", "url": "https://pubmed.ncbi.nlm.nih.gov/16878134/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID16878134", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC4" ] }, { "n": 2, "citation": "Guelen L, Pagie L, Brasset E et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008.", "tier": "A", "kind": "primary", "pmid": "18463634", "doi": "10.1038/nature06947", "url": "https://pubmed.ncbi.nlm.nih.gov/18463634/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID18463634", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC4" ] }, { "n": 3, "citation": "Kind J, Pagie L, de Vries SS et al. Genome-wide maps of nuclear lamina interactions in single human cells. Cell. 2015.", "tier": "A", "kind": "primary", "pmid": "26365489", "doi": "10.1016/j.cell.2015.08.040", "url": "https://pubmed.ncbi.nlm.nih.gov/26365489/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26365489", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC4" ] }, { "n": 4, "citation": "Shah PP, Keough KC, Gjoni K et al. An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype. Genome biology. 2023.", "tier": "A", "kind": "primary", "pmid": "36691074", "doi": "10.1186/s13059-023-02849-5", "url": "https://pubmed.ncbi.nlm.nih.gov/36691074/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36691074", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC4" ] }, { "n": 5, "citation": "Kind J, Pagie L, Ortabozkoyun H et al. Single-cell dynamics of genome-nuclear lamina interactions. Cell. 2013.", "tier": "A", "kind": "primary", "pmid": "23523135", "doi": "10.1016/j.cell.2013.02.028", "url": "https://pubmed.ncbi.nlm.nih.gov/23523135/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23523135", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC2", "CSC3" ] }, { "n": 6, "citation": "Reddy KL, Zullo JM, Bertolino E et al. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature. 2008.", "tier": "A", "kind": "primary", "pmid": "18272965", "doi": "10.1038/nature06727", "url": "https://pubmed.ncbi.nlm.nih.gov/18272965/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID18272965", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2", "CSC3", "CSC4" ] }, { "n": 7, "citation": "Kumaran RI, Spector DL. A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence. The Journal of cell biology. 2008.", "tier": "A", "kind": "primary", "pmid": "18195101", "doi": "10.1083/jcb.200706060", "url": "https://pubmed.ncbi.nlm.nih.gov/18195101/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID18195101", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph17, 1:Results:paragraph20. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC3", "CSC4" ] }, { "n": 8, "citation": "Leemans C, van der Zwalm MCH, Brueckner L et al. Promoter-Intrinsic and Local Chromatin Features Determine Gene Repression in LADs. Cell. 2019.", "tier": "A", "kind": "primary", "pmid": "30982597", "doi": "10.1016/j.cell.2019.03.009", "url": "https://pubmed.ncbi.nlm.nih.gov/30982597/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30982597", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1", "CSC3", "CSC4" ] }, { "n": 9, "citation": "Manzo SG, Mazouzi A, Leemans C et al. Chromatin protein complexes involved in gene repression in lamina-associated domains. The EMBO journal. 2024.", "tier": "A", "kind": "primary", "pmid": "39322756", "doi": "10.1038/s44318-024-00214-1", "url": "https://pubmed.ncbi.nlm.nih.gov/39322756/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39322756", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph14, 1:Results:paragraph22, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC3", "CSC4", "CH" ] }, { "n": 10, "citation": "Milon BC, Cheng H, Tselebrovsky MV et al. Role of histone deacetylases in gene regulation at nuclear lamina. PloS one. 2012.", "tier": "A", "kind": "primary", "pmid": "23226217", "doi": "10.1371/journal.pone.0049692", "url": "https://pubmed.ncbi.nlm.nih.gov/23226217/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23226217", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results and Discussion:paragraph0, 2:Results and Discussion:paragraph2, 2:Results and Discussion:paragraph4, 2:Results and Discussion:paragraph6, 2:Results and Discussion:paragraph8. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC2", "CSC3", "CH" ] }, { "n": 11, "citation": "Madsen-Østerbye J, Abdelhalim M, Pickering SH et al. Gene Regulatory Interactions at Lamina-Associated Domains. Genes. 2023.", "tier": "A", "kind": "primary", "pmid": "36833261", "doi": "10.3390/genes14020334", "url": "https://pubmed.ncbi.nlm.nih.gov/36833261/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36833261", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1", "CSC2", "CSC3" ] }, { "n": 12, "citation": "Robson MI, de Las Heras JI, Czapiewski R et al. Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis. Molecular cell. 2016.", "tier": "A", "kind": "primary", "pmid": "27264872", "doi": "10.1016/j.molcel.2016.04.035", "url": "https://pubmed.ncbi.nlm.nih.gov/27264872/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27264872", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC2", "CSC3" ] }, { "n": 13, "citation": "Smith CL, Poleshko A, Epstein JA. The nuclear periphery is a scaffold for tissue-specific enhancers. Nucleic acids research. 2021.", "tier": "A", "kind": "primary", "pmid": "34023908", "doi": "10.1093/nar/gkab392", "url": "https://pubmed.ncbi.nlm.nih.gov/34023908/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34023908", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC1", "CSC4" ] }, { "n": 14, "citation": "Heinz KS, Casas-Delucchi CS, Török T et al. Peripheral re-localization of constitutive heterochromatin advances its replication timing and impairs maintenance of silencing marks. Nucleic acids research. 2018.", "tier": "A", "kind": "primary", "pmid": "29750270", "doi": "10.1093/nar/gky368", "url": "https://pubmed.ncbi.nlm.nih.gov/29750270/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29750270", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC2", "CSC3", "CSC4" ] }, { "n": 15, "citation": "Kim Y, Sharov AA, McDole K et al. Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. 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Nucleic acids research. 2026.", "tier": "A", "kind": "primary", "pmid": "41909953", "doi": "10.1093/nar/gkag283", "url": "https://pubmed.ncbi.nlm.nih.gov/41909953/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41909953", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph1, 2:Results:paragraph0, 2:Results:paragraph5, 2:Results:paragraph31, 2:Results:paragraph32. No complete-paper or supplement audit claimed.", "carries_claims": [ "C60", "CSC2", "CSC3", "CSC4" ] } ], "independence_basis": { "required": false, "lines": [ { "label": "Native lamin loss and restoration", "sources": [ 17, 23, 25 ], "excludes_error": "Genetic loss and rescue reduce unperturbed co-localization explanations, with cell-state and whole-protein pleiotropy remaining." }, { "label": "Envelope-tether deconvolution", "sources": [ 26, 27, 12 ], "excludes_error": "Separates filament loss from membrane-tether redundancy; loss duration and differentiation effects still confound direct transcription mediation." }, { "label": "Silencing versus anchoring separations", "sources": [ 10, 33, 35, 9 ], "excludes_error": "Tests whether the same proteins or modifications are required for position and output, revealing causal decoupling and promoter-context alternatives." }, { "label": "Mechanics and motor signaling", "sources": [ 39, 41, 44 ], "excludes_error": "Orthogonal mechanical/actin/stress endpoints constrain direct-silencing interpretations, without eliminating all architecture effects." } ], "shared_failure_mode_checked": true, "note": "Hi-C, DamID, FISH and RNA readouts of the same lamin-null cells are complementary assays, not automatically independent causal lines. The2011/2018mESC series shares a model and related laboratory; PRR14 domain/localization follow-ups share a tether system. Human cardiomyopathy/progeria and worm disease models are not ordinary all-state replication. Updated2026and2025papers replace their earlier preprints. Simulated LAD attachment is not another perturbation line. Orthogonal classes reveal real context causality and real alternatives, not convergence on the global nominal." }, "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/lamins-transcriptional-repression-mechanisms/QKKFuu3RReuV471jflJXMw/" ], "query_record_note": "Exact visible question/response retained privately in raw browser receipt.", "primary_comparison_count": 9, "primary_comparisons": [ { "pmid": "30201095", "doi": "10.1016/j.molcel.2018.05.017", "source_type": "primary study report", "study_group": "MOUSE_LAMIN_NULL_ESC_SERIES", "access_depth": "full_text_partial", "consensus_aspect": "Consensus says major lamin loss does not cause global LAD derepression and links Zheng as2017.", "result_comparison": "Original2018publication Results confirms matched cell-cycle profiles, topology changes and partial laminB1add-back rescue, but no enrichment for expression changes among NL-associated genes. Detached LAD genes are not preferentially upregulated. Its publication-year2018is preserved separately from the provider's2017label; the source is not simply a transcriptional null.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/30201095/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-15-30-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\30201095-s1-p0-4-15-17.json" ] }, { "pmid": "22116031", "doi": "10.1126/science.1211222", "source_type": "primary study report", "study_group": "MOUSE_LAMIN_NULL_ESC_SERIES", "access_depth": "full_text_partial", "consensus_aspect": "Provider emphasizes lamin-null stem-cell exceptions.", "result_comparison": "Original body verifies ESC growth/pluripotency and induced TE differentiation without detectable laminA/C orB, with no relationship between bound promoters and RNA changes. This is a defined native context and does not imply every tissue is lamin-independent.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/22116031/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-15-30-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\22116031-s1-p3-4-9.json" ] }, { "pmid": "41735607", "doi": "10.1038/s41556-025-01822-7", "source_type": "primary study report", "study_group": "PMID41735607", "access_depth": "full_text_partial", "consensus_aspect": "Consensus contrasts mild72hourRNAchange with major chronic LBR/LAP2KOeffects.", "result_comparison": "Original body agrees and identifies membrane-tether redundancy. Additional B-lamin depletion does not enhance the defined LBR/LAP2 loss phenotype. Long-term transcriptome changes include stress/TF amplification and mixed directions; weak H3K27me3-expression correlation does not establish a recruited-enzyme mechanism.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41735607/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-15-30-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\41735607-s1-p12-19-23-32.json" ] }, { "pmid": "39322756", "doi": "10.1038/s44318-024-00214-1", "source_type": "primary study report", "study_group": "PMID39322756", "access_depth": "full_text_partial", "consensus_aspect": "Provider uses the2024LADscreen as evidence for chromatin regulators rather than lamin-only repression.", "result_comparison": "Original Results retains a modest LMNB1hit inLAD5and null inLAD6, inability to exclude essential/redundant factors, and NELF native-RNAeffects whose apparent LAD preference reduces after expression matching. The screen cannot be declared a universal proof of no lamin contribution.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/39322756/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-0-15-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\39322756-s1-p9-14-22-24-25.json" ] }, { "pmid": "23226217", "doi": "10.1371/journal.pone.0049692", "source_type": "primary study report", "study_group": "PMID23226217", "access_depth": "full_text_partial", "consensus_aspect": "Provider discusses local enzymatic repressors but does not detail the named flyHDACmechanistic split.", "result_comparison": "Original Results showsHDAC1silencing with no significant contact loss,HDAC3contact loss without comparable repression, and redundant LEM effects. It supports local causality while separating enzyme necessity from lamina-specific recruitment necessity.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/23226217/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-0-15-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\23226217-s2-p0-2-4-6-8.json" ] }, { "pmid": "36333314", "doi": "10.1038/s41467-022-34366-7", "source_type": "primary study report", "study_group": "PMID36333314", "access_depth": "full_text_partial", "consensus_aspect": "The requested Gata4-rescue/stem-state primary is not materially discussed in the observed synthesis.", "result_comparison": "Original Results showsGata4reduction/allele rescue and opposite effects whenA-type lamins are depleted in naive stem versus progenitor/cardiomyocyte stages. B1lossdoes not largely mimic cardiac differentiation. Contextual lamina regulation survives the global-repression challenge.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/36333314/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-15-30-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\36333314-s1-p5-27-41-43.json" ] }, { "pmid": "18195101", "doi": "10.1083/jcb.200706060", "source_type": "primary study report", "study_group": "PMID18195101", "access_depth": "full_text_partial", "consensus_aspect": "Consensus says synthetic peripheral tethering is sometimes sufficient and not decisive.", "result_comparison": "Original body defines a4Mbmulticopytransgene array whose peripheral transcription can be induced with similar kinetics. This is a meaningful synthetic countertest to universal position-silencing, but it is not every native gene and must remain labeled artificial.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/18195101/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-0-15-2800.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\18195101-s1-p0-17-20.json" ] }, { "pmid": "41909953", "doi": "10.1093/nar/gkag283", "source_type": "primary study report", "study_group": "PMID41909953", "access_depth": "full_text_partial", "consensus_aspect": "Consensus supplies a new2026B-lamin/speckle primary and reports more-than-half lower nascentRNA.", "result_comparison": "Original primary record and selectedMethods/Results verify the2026peer-reviewed paper: H1299CRISPR clones, lower nascentRNA, correlated speckle-distance/RNAchanges and increased death/apoptosis with reduced proliferation. Selectedbodyalso notes shRNA apoptosis replication. The source was added to the corpus as an actual examined lead; a selective speckle-distance mediator is not independently isolated.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/41909953/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-59-60-8000.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\41909953-s1-p0-1.json", "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\body-presentation-receipts\\41909953-s2-p0-5-31-32.json" ] }, { "pmid": "40335054", "doi": "10.1093/genetics/iyaf086", "source_type": "primary study report", "study_group": "PMID40335054", "access_depth": "abstract_metadata", "consensus_aspect": "The requested worm anchoring/mechanics primary is not detailed by the provider.", "result_comparison": "Original updated2025abstract showsCEC4lossaffects constrained nuclear migration in aLINC-defectivecontext and a lamin-stabilizing mutation rescues. Anchoring has a mechanical role; this cannot be converted to global transcriptional repression. Its earlier2024preprint is excluded from separate primary credit.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/40335054/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\examinations\\original-30-45-2800.json" ], "body_receipts": [] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\nuclear-lamina\\consensus-browser-2026-10-12.json", "sha256": "089c3bde136968628bedb5b96c5d3daa3221982527ce57715c92cac73ec999ad" } ], "independent_blinded_audit": false, "cutoff": "2026-10-09", "completed_utc": "2026-10-12T20:10:07.590764+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }