{
  "abstract": "Enhancers are key drivers of gene regulation thought to act via 3D physical interactions with the promoters of their target genes. However, genome-wide depletions of architectural proteins such as cohesin result in only limited changes in gene expression, despite a loss of contact domains and loops. Consequently, the role of cohesin and 3D contacts in enhancer function remains debated. Here, we developed CRISPRi of regulatory elements upon degron operation (CRUDO), a novel approach to measure how changes in contact frequency impact enhancer effects on target genes by perturbing enhancers with CRISPRi and measuring gene expression in the presence or absence of cohesin. We systematically perturbed all 1,039 candidate enhancers near five cohesin-dependent genes and identified 34 enhancer-gene regulatory interactions. Of 26 regulatory interactions with sufficient statistical power to evaluate cohesin dependence, 18 show cohesin-dependent effects. A decrease in enhancer-promoter contact frequency upon removal of cohesin is frequently accompanied by a decrease in the regulatory effect of the enhancer on gene expression, consistent with a contact-based model for enhancer function. However, changes in contact frequency and regulatory effects on gene expression vary as a function of distance, with distal enhancers (e.g., >50Kb) experiencing much larger changes than proximal ones (e.g., <50Kb). Because most enhancers are located close to their target genes, these observations can explain how only a small subset of genes - those with strong distal enhancers - are sensitive to cohesin. Together, our results illuminate how 3D contacts, influenced by both cohesin and genomic distance, tune enhancer effects on gene expression.",
  "abstract_shown": true,
  "affiliations": [
    "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany",
    "Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany",
    "Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA",
    "The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Department of Medicine, University of California San Francisco, San Francisco, CA, USA",
    "Department of Structural Biology, Stanford University, Stanford, CA, USA",
    "The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA",
    "Basic Sciences and Engineering Initiative, Betty Irene Moore Children’s Heart Center, Lucile Packard Children’s Hospital, Stanford, CA, USA",
    "Department of Computer Science, Stanford University, Stanford, CA, USA",
    "Department of Bioengineering, Stanford University, Stanford, CA, USA",
    "Department of Plant Biology, Carnegie Institute of Science, Stanford, CA, USA",
    "Center for Theoretical Biological Physics, Rice University, Houston, TX, USA",
    "Medical Student Training Program, Baylor College of Medicine, Houston, TX, USA",
    "Department of Computer Science, Rice University, Houston, TX, USA",
    "Department of BioSciences, Rice University, Houston, TX, USA",
    "European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany",
    "Stanford Genome Technology Center, Palo Alto, CA, USA",
    "Department of Biological Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan",
    "Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Yata 1111, Shizuoka, Mishima 411-8540, Japan",
    "Graduate Institute for Advanced Studies, SOKENDAI, Yata 1111, Shizuoka, Mishima 411-8540, Japan",
    "Department of Biology, MIT, Cambridge, MA, USA",
    "Department of Systems Biology, Harvard Medical School, Boston, MA, US",
    "Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 29,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Philine Guckelberger",
      "orcid": "0000-0002-1057-2518"
    },
    {
      "affs": [
        3
      ],
      "name": "Benjamin R. Doughty",
      "orcid": "0000-0003-0447-4468"
    },
    {
      "affs": [
        4
      ],
      "name": "Glen Munson"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Suhas S.P. Rao",
      "orcid": "0009-0002-2353-3371"
    },
    {
      "affs": [
        8,
        9,
        3
      ],
      "name": "Yingxuan Tan",
      "orcid": "0000-0001-6674-3219"
    },
    {
      "affs": [
        8,
        10,
        3
      ],
      "name": "Xiangmeng Shawn Cai",
      "orcid": "0000-0002-2466-4210"
    },
    {
      "affs": [
        0
      ],
      "name": "Charles P. Fulco",
      "orcid": "0000-0002-6592-1279"
    },
    {
      "affs": [
        0
      ],
      "name": "Joseph Nasser",
      "orcid": "0000-0001-5941-5751"
    },
    {
      "affs": [
        3,
        11
      ],
      "name": "Kristy S. Mualim",
      "orcid": "0000-0002-6898-3205"
    },
    {
      "affs": [
        0
      ],
      "name": "Drew T. Bergman",
      "orcid": "0000-0002-8314-7088"
    },
    {
      "affs": [
        4
      ],
      "name": "Judhajeet Ray",
      "orcid": "0000-0003-1524-2603"
    },
    {
      "affs": [
        4
      ],
      "name": "Evelyn Jagoda"
    },
    {
      "affs": [
        8,
        3
      ],
      "name": "Chad J. Munger",
      "orcid": "0000-0003-1906-1164"
    },
    {
      "affs": [
        8,
        3
      ],
      "name": "Andreas R. Gschwind",
      "orcid": "0000-0002-0769-6907"
    },
    {
      "affs": [
        8,
        10,
        3
      ],
      "name": "Maya U. Sheth",
      "orcid": "0000-0003-1466-8899"
    },
    {
      "affs": [
        8,
        3
      ],
      "name": "Anthony S. Tan"
    },
    {
      "affs": [
        12,
        7
      ],
      "name": "Saul Godinez Pulido",
      "orcid": "0000-0003-2111-5491"
    },
    {
      "affs": [
        12,
        7
      ],
      "name": "Namita Mitra",
      "orcid": "0000-0003-0654-0043"
    },
    {
      "affs": [
        12,
        7
      ],
      "name": "David Weisz",
      "orcid": "0000-0001-5868-6672"
    },
    {
      "affs": [
        12,
        13,
        7
      ],
      "name": "Muhammad S. Shamim",
      "orcid": "0000-0002-2600-5147"
    },
    {
      "affs": [
        0,
        14,
        7
      ],
      "name": "Neva C. Durand",
      "orcid": "0009-0006-5647-2623"
    },
    {
      "affs": [
        12,
        15,
        7
      ],
      "name": "Ragini Mahajan",
      "orcid": "0000-0002-1038-0698"
    },
    {
      "affs": [
        12,
        7
      ],
      "name": "Ruqayya Khan",
      "orcid": "0000-0001-7549-8761"
    },
    {
      "affs": [
        3,
        16,
        17
      ],
      "name": "Lars Michael Steinmetz",
      "orcid": "0000-0002-3962-2865"
    },
    {
      "affs": [
        18,
        19,
        20
      ],
      "name": "Masato T. Kanemaki",
      "orcid": "0000-0002-7657-1649"
    },
    {
      "affs": [
        0,
        21,
        22
      ],
      "name": "Eric S. Lander",
      "orcid": "0000-0003-2662-4631"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Alexander Meissner",
      "orcid": "0000-0001-8646-7469"
    },
    {
      "affs": [
        12,
        14,
        7
      ],
      "name": "Erez Lieberman Aiden",
      "orcid": "0000-0003-0634-6486"
    },
    {
      "affs": [
        8,
        3,
        23,
        24,
        4
      ],
      "name": "Jesse M. Engreitz"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ds48h90m5exkx.bib",
  "cited_by": 34,
  "doi": "10.1038/s41467-026-77582-1",
  "fulltext_url": "https://europepmc.org/articles/PMC13720136",
  "id": "ds48h90m5exkx",
  "issns": [
    "2041-1723"
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  "landing_url": "https://europepmc.org/article/MED/42957655",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
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  "pdf_url": "https://europepmc.org/articles/PMC13720136?pdf=render",
  "pmcid": "PMC13720136",
  "pmid": "42957655",
  "published": "2026-09-29",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/ds48h90m5exkx.ris",
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      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
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  ],
  "title": "Quantitative changes in 3D contact predict changes in enhancer-promoter regulation upon cohesin depletion.",
  "title_text": "Quantitative changes in 3D contact predict changes in enhancer-promoter regulation upon cohesin depletion.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:41Z",
  "url": "https://research.draconitic.com/paper/ds48h90m5exkx",
  "venue": "Nature communications",
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}