{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "18820678",
      "year": "2008",
      "title": "Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs.",
      "doi": "10.1038/nature07348",
      "url": "https://pubmed.ncbi.nlm.nih.gov/18820678/",
      "interpretation": "2008:local upstream ncRNA transcription is required for fbp1 chromatin opening in fission yeast, demonstrating a reverse-direction route."
    },
    {
      "pmid": "25849900",
      "year": "2015",
      "title": "Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers.",
      "doi": "10.1038/nbt.3199",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25849900/",
      "interpretation": "2015:targeted p300 acetyltransferase activates endogenous genes; artificial acetylation/coactivator recruitment is separated from opening alone."
    },
    {
      "pmid": "28287392",
      "year": "2017",
      "title": "The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells.",
      "doi": "10.7554/eLife.22631",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28287392/",
      "interpretation": "2017:OCT4 requires BRG1 for selected regulatory-element function in mouseESCs, mapping pioneer/remodeler cooperation."
    },
    {
      "pmid": "31126739",
      "year": "2019",
      "title": "Transcription Restart Establishes Chromatin Accessibility after DNA Replication.",
      "doi": "10.1016/j.molcel.2019.04.033",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31126739/",
      "interpretation": "2019:repli-ATAC and transcription inhibition show transcription restart contributes to postreplication accessibility restoration."
    },
    {
      "pmid": "31940339",
      "year": "2020",
      "title": "Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation.",
      "doi": "10.1371/journal.pgen.1008546",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31940339/",
      "interpretation": "2020:early zebrafish opening precedes activation and largely survives transcription inhibition, with miR430 as an exception."
    },
    {
      "pmid": "33558760",
      "year": "2021",
      "title": "Acute BAF perturbation causes immediate changes in chromatin accessibility.",
      "doi": "10.1038/s41588-021-00777-3",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33558760/",
      "interpretation": "2021:acute BAF degradation/ATPase inhibition identifies minute-scale accessibility maintenance; early transcription effects and tag baselines require separate interpretation."
    },
    {
      "pmid": "35182480",
      "year": "2022",
      "title": "The landscape of pioneer factor activity reveals the mechanisms of chromatin reprogramming and genome activation.",
      "doi": "10.1016/j.molcel.2022.01.024",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35182480/",
      "interpretation": "2022:targeted active/dead HAT contrasts show opening alone can fail to activate an endogenous target during ZGA."
    },
    {
      "pmid": "37922899",
      "year": "2023",
      "title": "Global identification of SWI/SNF targets reveals compensation by EP400.",
      "doi": "10.1016/j.cell.2023.10.006",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37922899/",
      "interpretation": "2023:EP400 compensation restores many promoter states/outputs; paused-polymerase/BAF work published2024(PMID38049663) strengthens bidirectional cooperation."
    },
    {
      "pmid": "40846763",
      "year": "2025",
      "title": "Precise modulation of BRG1 levels reveals features of mSWI/SNF dosage sensitivity.",
      "doi": "10.1038/s41588-025-02305-z",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40846763/",
      "interpretation": "2025:BRG1 dose manipulation shows enhancer sensitivity and buffered transcription, refining a simple one-to-one access model."
    },
    {
      "pmid": "42056506",
      "year": "2026",
      "title": "Pervasive and programmed nucleosome distortion on single chromatin fibres.",
      "doi": "10.1038/s41586-026-10418-6",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42056506/",
      "interpretation": "2026:single-fiber nucleosome-distortion and factor-domain experiments refine the physical meaning of molecular DNA access."
    }
  ],
  "gaps": [
    "A selective accessible-state necessity intervention must preserve the multifunctional regulators that establish it.",
    "Competence requires a standardized activating challenge and cannot be inferred from either basal ATAC or basal RNA alone.",
    "Bulk ATAC/DNase, methylase footprinting, local nucleosome distortion and large-scale decondensation measure different aspects of access.",
    "Temporal direction depends on developmental, replication and stimulus context; a universal upstream or downstream account fails.",
    "Specificity of factor/remodeler perturbations must exclude cell-cycle, viability, replication stress and transcriptional-collapse alternatives at each sampled time.",
    "Opening-only sufficiency fails at named loci, while acetylation/coactivator rescue can work; these need independent locus/state replication.",
    "Preprint/update duplication, shared reagents and repeated loci must be distinguished from independent error classes."
  ],
  "decisive_experiment": "At prespecified native promoters/enhancers, alter DNA accessibility with an orthogonal state intervention while preserving factor occupancy, activation domains, acetylation/coactivators and polymerase function as far as possible. Apply a matched activating stimulus and measure initiation/bursting with calibrated nascent RNA and single-fiber accessibility. Restore only the accessible state in a matched rescue; retain a dead-HAT opening-without-activation control. Verify cell-cycle distribution, replication stress, viability, target-factor abundance and local cis sequence across developmental/replication windows."
}