# Research timeline and gaps: Enhancer–Promoter Looping as Causal

Selected publication milestones, not an exhaustive history or discovery priority claim.

**2012 — Active tethering tests functional globin loop sufficiency.** [Original PMID22682246](https://pubmed.ncbi.nlm.nih.gov/22682246/).

**2014 — Loop-competent mutant separates proximity from activation chemistry.** [Original PMID24874989](https://pubmed.ncbi.nlm.nih.gov/24874989/).

**2016 — Forced globin contacts increase snapshot burst fraction.** [Original PMID27067601](https://pubmed.ncbi.nlm.nih.gov/27067601/).

**2019 — Live Sox2 distances fail to predict enhancer-dependent bursts.** [Original PMID31124784](https://pubmed.ncbi.nlm.nih.gov/31124784/).

**2019 — Neural Shh activation increases measured enhancer separation.** [Original PMID31494034](https://pubmed.ncbi.nlm.nih.gov/31494034/).

**2022 — Most enhancer contacts persist after acute architectural-factor loss.** [Original PMID36471071](https://pubmed.ncbi.nlm.nih.gov/36471071/).

**2024 — Ligation contact enrichment and spatial distance respond differently to activation.** [Original PMID38781242](https://pubmed.ncbi.nlm.nih.gov/38781242/).

**2026 — Live engineered landscapes resolve clusters of transcriptional bursts.** [Original PMID42449150](https://pubmed.ncbi.nlm.nih.gov/42449150/).

## Research gaps

Resolve fleeting productive encounters versus sustained molecular contact with calibrated label offsets and subsecond detection.

Separate burst frequency, burst occupancy, burst-cluster entry and active duration using live kinetics.

Develop contact-selective perturbation with enhancer and polymerase chemistry preserved.

Quantify transcriptional memory after contacts end at native loci.

Test initiation and maintenance separately in naive versus induced states and differentiated cells.

Reconcile assay-specific ligation enrichment and physical-distance distributions.

Audit the Du and Narita correction bodies and full supplements before publication-grade quantitative claims.

## Boundary experiment

At several prespecified native mammalian loci, combine molecular-resolution same-allele contact and nascent initiation tracking with rapidly reversible contact-selective tether release while preserving enhancer activity, local factor occupancy and transcriptional competence.