{
  "abstract": "Most of the human genome is thought to be non-functional, and includes large segments often referred to as \"dark matter\" DNA. The genome also encodes hundreds of putative and poorly characterized transcription factors (TFs). We determined genomic binding locations of 166 uncharacterized human TFs in living cells. Nearly half of them associated strongly with known regulatory regions such as promoters and enhancers, often at conserved motif matches and co-localizing with each other. Surprisingly, the other half often associated with genomic dark matter, at largely unique sites, via intrinsic sequence recognition. Dozens of these, which we term \"Dark TFs\", mainly bind within regions of closed chromatin. Dark TF binding sites are enriched for transposable elements, and are rarely under purifying selection. Some Dark TFs are KZNFs, which contain the repressive KRAB domain, but many are not: the Dark TFs also include known or potential pioneer TFs. Compiled literature information supports that the Dark TFs exert diverse functions ranging from early development to tumor suppression. Thus, our results sheds light on a large fraction of previously uncharacterized human TFs and their unappreciated activities within the dark matter genome.",
  "abstract_shown": true,
  "affiliations": [
    "Donnelly Centre and Department of Molecular Genetics, Toronto, ON, Canada",
    "Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA",
    "Victor P. Dahdaleh Institute of Genomic Medicine, Montréal, QC, Canada",
    "Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia",
    "Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland",
    "Swiss Institute of Bioinformatics, Lausanne, Switzerland",
    "Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada",
    "Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle, Germany",
    "Bioinformatics Laboratory, Federal Research Center for Information and Computational Technologies, Novosibirsk, Russia",
    "Department of Computational Biology, Sirius University of Science and Technology, Sirius, Russia",
    "Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia",
    "Bioinformatics Competence Center, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland",
    "Bioinformatics Competence Center, Université de Lausanne, Lausanne, Switzerland",
    "Chugai Pharmaceutical Co., Ltd, Tokyo, Japan",
    "Biosoft.Ru LLC, Novosibirsk, Russia",
    "Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia",
    "Computer Science Institute, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic",
    "Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic",
    "Max Planck Institute of Biochemistry, Planegg, Germany",
    "Altius Institute for Biomedical Sciences, Seattle, WA, USA",
    "Biotechnologisches Zentrum (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), TUD Dresden University of Technology, Dresden, Germany",
    "Cincinnati Children’s Hospital, Cincinnati, OH, USA",
    "Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, Ufa, Russia",
    "Department of Human Genetics, McGill University, Montréal, QC, Canada",
    "Donnelly Centre and Department of Molecular Genetics, Toronto, ON, Canada. t.hughes@utoronto.ca"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 51,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rozita Razavi",
      "orcid": "0009-0000-5466-6519"
    },
    {
      "affs": [
        0
      ],
      "name": "Ali Fathi",
      "orcid": "0009-0007-1441-9653"
    },
    {
      "affs": [
        0
      ],
      "name": "Isaac Yellan",
      "orcid": "0000-0001-6622-1189"
    },
    {
      "affs": [
        0
      ],
      "name": "Alexander V. Brechalov",
      "orcid": "0000-0003-0540-4517"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kaitlin U. Laverty",
      "orcid": "0009-0004-4341-4665"
    },
    {
      "affs": [
        0
      ],
      "name": "Arttu Jolma",
      "orcid": "0000-0002-2543-7490"
    },
    {
      "affs": [
        2
      ],
      "name": "Aldo Hernández-Corchado",
      "orcid": "0000-0003-0682-3959"
    },
    {
      "affs": [
        0
      ],
      "name": "Hong Zheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Ally W. H. Yang",
      "orcid": "0000-0002-8678-0946"
    },
    {
      "affs": [
        0
      ],
      "name": "Mihai Albu",
      "orcid": "0009-0000-8417-681X"
    },
    {
      "affs": [
        0
      ],
      "name": "Marjan Barazandeh",
      "orcid": "0000-0003-3420-3669"
    },
    {
      "affs": [
        0
      ],
      "name": "Chun Hu"
    },
    {
      "affs": [
        3
      ],
      "name": "Ilya E. Vorontsov",
      "orcid": "0000-0001-8888-0804"
    },
    {
      "affs": [
        0
      ],
      "name": "Zain M. Patel"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Bart Deplancke",
      "orcid": "0000-0001-9935-843X"
    },
    {
      "affs": [
        6
      ],
      "name": "Oriol Fornés",
      "orcid": "0000-0002-5969-3054"
    },
    {
      "affs": [
        7
      ],
      "name": "Jan Grau",
      "orcid": "0000-0003-2081-6405"
    },
    {
      "affs": [
        7
      ],
      "name": "Ivo Große",
      "orcid": "0000-0001-5318-4825"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Fedor A. Kolpakov"
    },
    {
      "affs": [
        3
      ],
      "name": "Vsevolod J. Makeev",
      "orcid": "0000-0001-9405-9748"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhenfeng Deng"
    },
    {
      "affs": [
        0
      ],
      "name": "Samuel A. Lambert",
      "orcid": "0000-0001-8222-008X"
    },
    {
      "affs": [
        0
      ],
      "name": "Sara E. Pour",
      "orcid": "0009-0009-6201-1921"
    },
    {
      "affs": [
        0
      ],
      "name": "Mikhail Salnikov"
    },
    {
      "affs": [
        10
      ],
      "name": "Georgy Meshcheryakov"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Giovanna Ambrosini",
      "orcid": "0000-0003-1294-6541"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Antoni J. Gralak",
      "orcid": "0009-0007-1086-6165"
    },
    {
      "affs": [
        13
      ],
      "name": "Sachi Inukai",
      "orcid": "0000-0002-6404-1384"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Judith F. Kribelbauer-Swietek",
      "orcid": "0000-0002-8072-7773"
    },
    {
      "affs": [
        7
      ],
      "name": "Marie-Luise Plescher",
      "orcid": "0009-0006-6163-9782"
    },
    {
      "affs": [
        9
      ],
      "name": "Semyon K. Kolmykov",
      "orcid": "0000-0002-9259-0495"
    },
    {
      "affs": [
        14
      ],
      "name": "Ivan Yevshin"
    },
    {
      "affs": [
        10
      ],
      "name": "Nikita Gryzunov",
      "orcid": "0009-0000-0782-8650"
    },
    {
      "affs": [
        15,
        3
      ],
      "name": "Ivan Kozin",
      "orcid": "0009-0009-4603-8550"
    },
    {
      "affs": [
        15
      ],
      "name": "Mikhail Nikonov"
    },
    {
      "affs": [
        15
      ],
      "name": "Vladimir Nozdrin",
      "orcid": "0009-0004-3053-1387"
    },
    {
      "affs": [
        15
      ],
      "name": "Arsenii O. Zinkevich",
      "orcid": "0000-0001-9450-4629"
    },
    {
      "affs": [
        16,
        17
      ],
      "name": "Kateřina Faltejsková",
      "orcid": "0000-0001-7390-8077"
    },
    {
      "affs": [
        18
      ],
      "name": "Pavel Kravchenko",
      "orcid": "0000-0002-5751-7129"
    },
    {
      "affs": [
        19,
        3
      ],
      "name": "Sergey Abramov",
      "orcid": "0000-0002-3334-5334"
    },
    {
      "affs": [
        19,
        3
      ],
      "name": "Alexandr Boytsov",
      "orcid": "0000-0002-2712-8368"
    },
    {
      "affs": [
        3
      ],
      "name": "Vasilii Kamenets"
    },
    {
      "affs": [
        15,
        3
      ],
      "name": "Dmitry Penzar"
    },
    {
      "affs": [
        20
      ],
      "name": "Anton Vlasov",
      "orcid": "0000-0001-8558-9763"
    },
    {
      "affs": [
        21
      ],
      "name": "Xiaoting Chen",
      "orcid": "0000-0002-3782-3962"
    },
    {
      "affs": [
        21
      ],
      "name": "Matthew T. Weirauch",
      "orcid": "0000-0001-7977-9122"
    },
    {
      "affs": [
        22,
        10,
        3
      ],
      "name": "Ivan V. Kulakovskiy",
      "orcid": "0000-0002-6554-8128"
    },
    {
      "affs": [
        5
      ],
      "name": "Philipp Bücher",
      "orcid": "0000-0003-4824-885X"
    },
    {
      "affs": [
        1
      ],
      "name": "Quaid Morris",
      "orcid": "0000-0002-2760-6999"
    },
    {
      "affs": [
        23,
        2
      ],
      "name": "Hamed Shateri Najafabadi",
      "orcid": "0000-0003-2735-4231"
    },
    {
      "affs": [
        24
      ],
      "name": "Timothy R. Hughes",
      "orcid": "0000-0002-8721-4719"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/078y83emb4zed.bib",
  "cited_by": 11,
  "doi": "10.1038/s41467-026-75376-z",
  "fulltext_url": null,
  "id": "078y83emb4zed",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-75376-z",
  "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": [
    [
      "openalex",
      "1312|Genomics and Chromatin Dynamics"
    ]
  ],
  "openalex": "W7172505510",
  "pdf_url": "https://www.nature.com/articles/s41467-026-75376-z.pdf",
  "pmcid": "PMC11601254",
  "pmid": "39605320",
  "published": "2026-08-05",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/078y83emb4zed.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:07Z",
      "native_id": "W7172505510",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41467-026-75376-z"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Extensive binding of poorly characterized human transcription factors to genomic dark matter",
  "title_text": "Extensive binding of poorly characterized human transcription factors to genomic dark matter",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T13:21:07Z",
  "url": "https://research.draconitic.com/paper/078y83emb4zed",
  "venue": "Nature Communications",
  "versions": []
}