{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "22682246",
      "year": "2012",
      "title": "Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor.",
      "doi": "10.1016/j.cell.2012.03.051",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22682246/",
      "interpretation": "Active tethering tests functional globin loop sufficiency."
    },
    {
      "pmid": "24874989",
      "year": "2014",
      "title": "Role of LDB1 in the transition from chromatin looping to transcription activation.",
      "doi": "10.1101/gad.239749.114",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24874989/",
      "interpretation": "Loop-competent mutant separates proximity from activation chemistry."
    },
    {
      "pmid": "27067601",
      "year": "2016",
      "title": "Enhancer Regulation of Transcriptional Bursting Parameters Revealed by Forced Chromatin Looping.",
      "doi": "10.1016/j.molcel.2016.03.007",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27067601/",
      "interpretation": "Forced globin contacts increase snapshot burst fraction."
    },
    {
      "pmid": "31124784",
      "year": "2019",
      "title": "Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity.",
      "doi": "10.7554/eLife.41769",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31124784/",
      "interpretation": "Live Sox2 distances fail to predict enhancer-dependent bursts."
    },
    {
      "pmid": "31494034",
      "year": "2019",
      "title": "Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation.",
      "doi": "10.1016/j.molcel.2019.07.038",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31494034/",
      "interpretation": "Neural Shh activation increases measured enhancer separation."
    },
    {
      "pmid": "36471071",
      "year": "2022",
      "title": "Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1.",
      "doi": "10.1038/s41588-022-01223-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36471071/",
      "interpretation": "Most enhancer contacts persist after acute architectural-factor loss."
    },
    {
      "pmid": "38781242",
      "year": "2024",
      "title": "Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity.",
      "doi": "10.1371/journal.pgen.1011277",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38781242/",
      "interpretation": "Ligation contact enrichment and spatial distance respond differently to activation."
    },
    {
      "pmid": "42449150",
      "year": "2026",
      "title": "Enhancer control of promoter activity and variability via frequency modulation of clustered transcriptional bursts.",
      "doi": "10.1038/s41588-026-02676-x",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42449150/",
      "interpretation": "Live engineered landscapes resolve clusters of transcriptional bursts."
    }
  ],
  "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."
  ],
  "decisive_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."
}