{
  "abstract": "Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease 1–6 . Here we create and evaluate a resource of more than 92 million enhancer–gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium 7 . We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element–gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer–gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer–promoter contacts, additional features that guide enhancer–promoter communication include promoter class and enhancer–enhancer synergy. These genome-wide maps of enhancer–gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.",
  "abstract_shown": true,
  "affiliations": [
    "Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA",
    "Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA",
    "Department of Plant Biology, Carnegie Institute of Science, Stanford, CA, USA",
    "Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA",
    "Department of Bioengineering, Stanford University, Stanford, CA, USA",
    "Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA",
    "Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain",
    "Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA",
    "McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA",
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Systems Biology, Harvard Medical School, Boston, MA, USA",
    "Google DeepMind, London, UK",
    "Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA",
    "Department of Pathology, Mass General Brigham, Boston, MA, USA",
    "Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA",
    "Department of Medicine, University of California San Francisco, San Francisco, CA, USA",
    "Department of Structural Biology, Stanford University, Stanford, CA, USA",
    "Center for Theoretical Biological Physics, Rice University, Houston, TX, USA",
    "Department of Biosciences, Rice University, Houston, TX, USA",
    "Artificial Intelligence Laboratory, Illumina Inc., San Diego, CA, USA",
    "Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA",
    "Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA",
    "Calico Life Sciences LLC, South San Francisco, CA, USA",
    "Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA",
    "Department of Medicine, Massachusetts General Hospital, Boston, MA, USA",
    "Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA",
    "Halıcıoğlu Data Science Institute, University of California San Diego, San Diego, CA, USA",
    "Altius Institute for Biomedical Sciences, Seattle, WA, USA",
    "Clinical Research Division, Fred Hutch Cancer Center, Seattle, WA, USA",
    "Department of Applied Physics, Stanford University, Stanford, CA, USA",
    "Memorial Sloan Kettering Cancer Center, New York, NY, USA",
    "European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany",
    "Stanford Genome Technology Center, Palo Alto, CA, USA",
    "Department of Computer Science, Stanford University, Stanford, CA, USA",
    "Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA. engreitz@stanford.edu",
    "Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. engreitz@stanford.edu",
    "Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. engreitz@stanford.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 46,
  "authors": [
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        0,
        1
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      "name": "Andreas R. Gschwind",
      "orcid": "0000-0002-0769-6907"
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    {
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        1,
        2
      ],
      "name": "Kristy S. Mualim",
      "orcid": "0000-0002-6898-3205"
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      "name": "Alireza Karbalayghareh",
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      "name": "Kushal K. Dey"
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      "name": "David Yao",
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      "name": "Judhajeet Ray",
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      "name": "Chad J. Munger",
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      "name": "Joseph Nasser",
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      "name": "Žiga Avsec",
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      "name": "Benjamin T. James",
      "orcid": "0000-0002-6228-055X"
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        15
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      "name": "Muhammad S. Shamim",
      "orcid": "0000-0002-2600-5147"
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      "name": "Neva C. Durand",
      "orcid": "0009-0006-5647-2623"
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      "name": "Suhas S.P. Rao",
      "orcid": "0009-0002-2353-3371"
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      "name": "Ragini Mahajan",
      "orcid": "0000-0002-1038-0698"
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    {
      "affs": [
        1
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      "name": "Benjamin R. Doughty",
      "orcid": "0000-0003-0447-4468"
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    {
      "affs": [
        1
      ],
      "name": "Kalina Andreeva",
      "orcid": "0000-0002-5206-532X"
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    {
      "affs": [
        21,
        11
      ],
      "name": "Jacob C. Ulirsch",
      "orcid": "0000-0002-7947-0827"
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    {
      "affs": [
        22,
        23
      ],
      "name": "Kaili Fan",
      "orcid": "0000-0002-8723-7902"
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    {
      "affs": [
        11
      ],
      "name": "Elizabeth M. Perez",
      "orcid": "0000-0002-6198-8329"
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    {
      "affs": [
        0,
        1
      ],
      "name": "Tri C. Nguyen",
      "orcid": "0000-0002-5141-5228"
    },
    {
      "affs": [
        24
      ],
      "name": "David R. Kelley",
      "orcid": "0000-0001-7782-3548"
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    {
      "affs": [
        25,
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        27
      ],
      "name": "Hilary K. Finucane",
      "orcid": "0000-0003-3864-9828"
    },
    {
      "affs": [
        23
      ],
      "name": "Jill E. Moore",
      "orcid": "0000-0002-3023-0806"
    },
    {
      "affs": [
        23
      ],
      "name": "Zhiping Weng",
      "orcid": "0000-0002-3032-7966"
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    {
      "affs": [
        11,
        14
      ],
      "name": "M Kellis",
      "orcid": "0000-0001-7113-9630"
    },
    {
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      "name": "Michael Cory Bassik",
      "orcid": "0000-0001-5185-8427"
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        29
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      "name": "Berk Ustun",
      "orcid": "0000-0001-5188-3155"
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        5
      ],
      "name": "Alkes L. Price",
      "orcid": "0000-0002-2971-7975"
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    {
      "affs": [
        9,
        10
      ],
      "name": "M Beer",
      "orcid": "0000-0001-9955-3809"
    },
    {
      "affs": [
        8
      ],
      "name": "Roderic Guigó",
      "orcid": "0000-0002-5738-4477"
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    {
      "affs": [
        30,
        31
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      "name": "John A. Stamatoyannopoulos",
      "orcid": "0000-0002-2664-5769"
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        16,
        20
      ],
      "name": "Erez Lieberman Aiden",
      "orcid": "0000-0003-0634-6486"
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    {
      "affs": [
        32,
        1
      ],
      "name": "William James Greenleaf",
      "orcid": "0000-0003-1409-3095"
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    {
      "affs": [
        33
      ],
      "name": "Christina S. Leslie",
      "orcid": "0000-0002-4571-5910"
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    {
      "affs": [
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        34,
        35
      ],
      "name": "Lars Michael Steinmetz",
      "orcid": "0000-0002-3962-2865"
    },
    {
      "affs": [
        36,
        1
      ],
      "name": "Anshul Bharat Kundaje",
      "orcid": "0000-0003-3084-2287"
    },
    {
      "affs": [
        37,
        38,
        39
      ],
      "name": "J Engreitz",
      "orcid": "0000-0002-5754-1719"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4w6exjz1d4gc4.bib",
  "cited_by": 152,
  "doi": "10.1038/s41586-026-10781-4",
  "fulltext_url": null,
  "id": "4w6exjz1d4gc4",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10781-4",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "1312|Genomics and Chromatin Dynamics"
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  "pdf_url": "https://www.nature.com/articles/s41586-026-10781-4.pdf",
  "pmcid": "PMC13471189",
  "pmid": "42457959",
  "published": "2026-07-15",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/4w6exjz1d4gc4.ris",
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    {
      "first_seen": "2026-10-30T13:26:46Z",
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      "url": "https://doi.org/10.1038/s41586-026-10781-4"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
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  ],
  "title": "An encyclopedia of human enhancer–gene regulatory interactions",
  "title_text": "An encyclopedia of human enhancer–gene regulatory interactions",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:05Z",
  "url": "https://research.draconitic.com/paper/4w6exjz1d4gc4",
  "venue": "Nature",
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