{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "23582322",
      "year": "2013",
      "title": "Master transcription factors and mediator establish super-enhancers at key cell identity genes.",
      "doi": "10.1016/j.cell.2013.03.035",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23582322/",
      "interpretation": "Operational Mediator-rich clusters are linked with cell-identity genes."
    },
    {
      "pmid": "25801169",
      "year": "2015",
      "title": "Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers.",
      "doi": "10.1016/j.molcel.2015.02.014",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25801169/",
      "interpretation": "Native constituent deletion identifies local regulatory interdependence."
    },
    {
      "pmid": "27376235",
      "year": "2016",
      "title": "Genetic dissection of the α-globin super-enhancer in vivo.",
      "doi": "10.1038/ng.3605",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27376235/",
      "interpretation": "Alpha-globin allelic series tests apparent additive contributions."
    },
    {
      "pmid": "27376239",
      "year": "2016",
      "title": "Hierarchy within the mammary STAT5-driven Wap super-enhancer.",
      "doi": "10.1038/ng.3606",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27376239/",
      "interpretation": "Mammary motif combinations distinguish hierarchy and tested pairwise addition."
    },
    {
      "pmid": "27895109",
      "year": "2017",
      "title": "Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes.",
      "doi": "10.1101/gr.210930.116",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27895109/",
      "interpretation": "Native conventional and called-cluster comparisons expose functional heterogeneity."
    },
    {
      "pmid": "31493975",
      "year": "2019",
      "title": "Nucleome Dynamics during Retinal Development.",
      "doi": "10.1016/j.neuron.2019.08.002",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31493975/",
      "interpretation": "Native retinal enhancer-region deletion changes cell composition and vision."
    },
    {
      "pmid": "38101409",
      "year": "2023",
      "title": "Super-enhancers include classical enhancers and facilitators to fully activate gene expression.",
      "doi": "10.1016/j.cell.2023.11.030",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38101409/",
      "interpretation": "Native reconstruction reveals activators and position-dependent facilitators."
    },
    {
      "pmid": "39863595",
      "year": "2025",
      "title": "The α-globin super-enhancer acts in an orientation-dependent manner.",
      "doi": "10.1038/s41467-025-56380-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39863595/",
      "interpretation": "Cluster inversion adds an endogenous orientation and targeting test."
    }
  ],
  "gaps": [
    "Test SEs against activity-, length-, constituent-number- and promoter-matched conventional clusters, rather than weak isolated enhancers.",
    "Use reconstruction and higher-order combinations to avoid missing interactions masked by single deletions.",
    "Separate transcriptional output, physiological specialization, lineage formation and maintenance of cell identity.",
    "Define a nonadditive null model on an explicit output scale, with uncertainty, saturation and promoter limits.",
    "Resolve facilitator position, sequence, promoter compatibility and developmental redundancy across independent loci.",
    "Separate coactivator protein dependence from condensate-phase-specific function and drug pleiotropy.",
    "Audit linked correction bodies for the alpha-globin inversion, Myc cluster, Gasperini screen and Du study before publication; resolve the muscle abstract descriptor inconsistency."
  ],
  "decisive_experiment": "Compare a prespecified multi-lineage panel of high-ChIP clusters and conventional clusters matched for constituent number, occupancy, baseline output, spacing and promoter compatibility using native combinatorial deletions and reconstruction with lineage-state tracking."
}