{
  "abstract": "Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs 1 . Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells 2 . Here we describe a systematic effort (‘Codebook’) to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome. These sites are concentrated in promoter regions and are predictive of gene expression. In summary, this new codebook provides an important step forward in decoding the human genome.",
  "abstract_shown": true,
  "affiliations": [
    "Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada",
    "Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA",
    "Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada",
    "Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, Moscow, Russia",
    "Chugai Pharmaceutical Co., Ltd, Tokyo, 103-8324, Japan",
    "Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland",
    "Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland",
    "Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA",
    "Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Divisions of Allergy and Immunology, Biomedical Informatics, Human Genetics, and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA",
    "Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia",
    "Institute of Protein Research, Russian Academy of Sciences, 142290, Pushchino, Russia",
    "Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada",
    "Institute of Computer Science, Martin Luther University Halle-Wittenberg, 06099, Halle, Germany",
    "Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, 450054, Ufa, Russia",
    "Bioinformatics Laboratory, Federal Research Center for Information and Computational Technologies, 630090, Novosibirsk, Russia",
    "Department of Computational Biology, Sirius University of Science and Technology, 354340, Sirius, Krasnodar region, Russia",
    "Bioinformatics Competence Center, Université de Lausanne, 1015 Lausanne, Switzerland"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 79,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Arttu Jolma",
      "orcid": "0000-0002-2543-7490"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kaitlin U. Laverty",
      "orcid": "0009-0004-4341-4665"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Ali Fathi",
      "orcid": "0009-0007-1441-9653"
    },
    {
      "affs": [
        0
      ],
      "name": "Ally W. H. Yang",
      "orcid": "0000-0002-8678-0946"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Isaac Yellan",
      "orcid": "0000-0001-6622-1189"
    },
    {
      "affs": [
        3
      ],
      "name": "Ilya E. Vorontsov",
      "orcid": "0000-0001-8888-0804"
    },
    {
      "affs": [
        4,
        5,
        6
      ],
      "name": "Sachi Inukai",
      "orcid": "0000-0002-6404-1384"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Judith F. Kribelbauer",
      "orcid": "0000-0002-8072-7773"
    },
    {
      "affs": [
        7,
        8,
        5,
        6
      ],
      "name": "Antoni J. Gralak",
      "orcid": "0009-0007-1086-6165"
    },
    {
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        0
      ],
      "name": "Rozita Razavi",
      "orcid": "0009-0000-5466-6519"
    },
    {
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        0
      ],
      "name": "Mihai Albu",
      "orcid": "0009-0000-8417-681X"
    },
    {
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      ],
      "name": "Alexander V. Brechalov",
      "orcid": "0000-0003-0540-4517"
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        0
      ],
      "name": "Zain M. Patel"
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      "name": "Vladimir Nozdrin",
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      "name": "G. A. Meshcheryakov",
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      "name": "Andrey Buyan",
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        10,
        3
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      "name": "Ivan Kozin",
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        3
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      "name": "Sergey Abramov",
      "orcid": "0000-0002-3334-5334"
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    {
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        7,
        3
      ],
      "name": "Alexandr Boytsov",
      "orcid": "0000-0002-2712-8368"
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      "affs": [
        8
      ],
      "name": "Matthew T. Weirauch",
      "orcid": "0000-0001-7977-9122"
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        11
      ],
      "name": "Oriol Fornés",
      "orcid": "0000-0002-5969-3054"
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        3
      ],
      "name": "Vsevolod J. Makeev",
      "orcid": "0000-0001-9405-9748"
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        12
      ],
      "name": "Jan Grau",
      "orcid": "0000-0003-2081-6405"
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      ],
      "name": "Ivo Große",
      "orcid": "0000-0001-5318-4825"
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      ],
      "name": "Philipp Bucher",
      "orcid": "0000-0003-4824-885X"
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    {
      "affs": [
        5,
        6
      ],
      "name": "Bart Deplancke",
      "orcid": "0000-0001-9935-843X"
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        12,
        10,
        3
      ],
      "name": "Ivan V. Kulakovskiy",
      "orcid": "0000-0002-6554-8128"
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    {
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        2,
        0
      ],
      "name": "Timothy P. Hughes",
      "orcid": "0000-0002-0910-3730"
    },
    {
      "affs": [
        6
      ],
      "name": "Philipp Bucher",
      "orcid": "0000-0003-4824-885X"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Bart Deplancke",
      "orcid": "0000-0001-9935-843X"
    },
    {
      "affs": [
        11
      ],
      "name": "Oriol Fornés",
      "orcid": "0000-0002-5969-3054"
    },
    {
      "affs": [
        12
      ],
      "name": "Jan Grau",
      "orcid": "0000-0003-2081-6405"
    },
    {
      "affs": [
        12
      ],
      "name": "Ivo Grosse"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Timothy R. Hughes"
    },
    {
      "affs": [
        0
      ],
      "name": "Arttu Jolma",
      "orcid": "0000-0002-2543-7490"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Fedor A. Kolpakov"
    },
    {
      "affs": [
        13,
        12,
        10,
        3
      ],
      "name": "Ivan V. Kulakovskiy",
      "orcid": "0000-0002-6554-8128"
    },
    {
      "affs": [
        3
      ],
      "name": "Vsevolod J. Makeev",
      "orcid": "0000-0001-9405-9748"
    },
    {
      "affs": [
        0
      ],
      "name": "Mihai Albu"
    },
    {
      "affs": [
        0
      ],
      "name": "Marjan Barazandeh",
      "orcid": "0000-0003-3420-3669"
    },
    {
      "affs": [
        0
      ],
      "name": "Alexander Brechalov"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhenfeng Deng"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Ali Fathi"
    },
    {
      "affs": [
        0
      ],
      "name": "Chun Hu"
    },
    {
      "affs": [
        0
      ],
      "name": "Samuel A. Lambert",
      "orcid": "0000-0001-8222-008X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kaitlin U. Laverty",
      "orcid": "0009-0004-4341-4665"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Zain M. Patel"
    },
    {
      "affs": [
        0
      ],
      "name": "Sara E. Pour",
      "orcid": "0009-0009-6201-1921"
    },
    {
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        0
      ],
      "name": "Rozita Razavi",
      "orcid": "0009-0000-5466-6519"
    },
    {
      "affs": [
        0
      ],
      "name": "Mikhail Salnikov"
    },
    {
      "affs": [
        0
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      "name": "Ally W. H. Yang",
      "orcid": "0000-0002-8678-0946"
    },
    {
      "affs": [
        2,
        0
      ],
      "name": "Isaac Yellan",
      "orcid": "0000-0001-6622-1189"
    },
    {
      "affs": [
        0
      ],
      "name": "Hong Zheng"
    },
    {
      "affs": [
        10,
        6
      ],
      "name": "Georgy Meshcheryakov"
    },
    {
      "affs": [
        16
      ],
      "name": "Giovanna Ambrosini",
      "orcid": "0000-0003-1294-6541"
    },
    {
      "affs": [
        7,
        8,
        5,
        6
      ],
      "name": "Antoni J. Gralak",
      "orcid": "0009-0007-1086-6165"
    },
    {
      "affs": [
        4,
        5,
        6
      ],
      "name": "Sachi Inukai",
      "orcid": "0000-0002-6404-1384"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Judith F. Kribelbauer",
      "orcid": "0000-0002-8072-7773"
    },
    {
      "affs": [
        12
      ],
      "name": "Marie-Luise Plescher",
      "orcid": "0009-0006-6163-9782"
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    {
      "affs": [
        15
      ],
      "name": "Semyon Kolmykov"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cznz8edk93vrh.bib",
  "cited_by": 14,
  "doi": "10.1038/s41586-026-10798-9",
  "fulltext_url": null,
  "id": "cznz8edk93vrh",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10798-9",
  "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": "W7172502384",
  "pdf_url": null,
  "pmcid": "PMC11601247",
  "pmid": "39605729",
  "published": "2026-08-05",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/cznz8edk93vrh.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:06Z",
      "native_id": "W7172502384",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10798-9"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "An expanded codebook of human transcription factor DNA-binding specificity",
  "title_text": "An expanded codebook of human transcription factor DNA-binding specificity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:05Z",
  "url": "https://research.draconitic.com/paper/cznz8edk93vrh",
  "venue": "Nature",
  "versions": []
}