Peer-reviewedCC BYNature
An expanded codebook of human transcription factor DNA-binding specificity
17 affiliations
- 1Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
- 2Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- 3Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
- 4Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, Moscow, Russia
- 5Chugai Pharmaceutical Co., Ltd, Tokyo, 103-8324, Japan
- 6Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
- 7Swiss Institute of Bioinformatics, 1015, Lausanne, Switzerland
- 8Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
- 9Center 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
- 10Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia
- 11Institute of Protein Research, Russian Academy of Sciences, 142290, Pushchino, Russia
- 12Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
- 13Institute of Computer Science, Martin Luther University Halle-Wittenberg, 06099, Halle, Germany
- 14Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, 450054, Ufa, Russia
- 15Bioinformatics Laboratory, Federal Research Center for Information and Computational Technologies, 630090, Novosibirsk, Russia
- 16Department of Computational Biology, Sirius University of Science and Technology, 354340, Sirius, Krasnodar region, Russia
- 17Bioinformatics Competence Center, Université de Lausanne, 1015 Lausanne, Switzerland
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.
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BibTeX
@article{jolma2026expanded,
title = {{An expanded codebook of human transcription factor DNA-binding specificity}},
author = {Arttu Jolma and Kaitlin U. Laverty and Ali Fathi and Ally W. H. Yang and Isaac Yellan and Ilya E. Vorontsov and Sachi Inukai and Judith F. Kribelbauer and Antoni J. Gralak and Rozita Razavi and Mihai Albu and Alexander V. Brechalov and Zain M. Patel and Vladimir Nozdrin and G. A. Meshcheryakov and Andrey Buyan and Ivan Kozin and Sergey Abramov and Alexandr Boytsov and Matthew T. Weirauch and Oriol Fornés and Vsevolod J. Makeev and Jan Grau and Ivo Große and Philipp Bucher and Bart Deplancke and Ivan V. Kulakovskiy and Timothy P. Hughes and Philipp Bucher and Bart Deplancke and Oriol Fornés and Jan Grau and Ivo Grosse and Timothy R. Hughes and Arttu Jolma and Fedor A. Kolpakov and Ivan V. Kulakovskiy and Vsevolod J. Makeev and Mihai Albu and Marjan Barazandeh and Alexander Brechalov and Zhenfeng Deng and Ali Fathi and Chun Hu and Samuel A. Lambert and Kaitlin U. Laverty and Zain M. Patel and Sara E. Pour and Rozita Razavi and Mikhail Salnikov and Ally W. H. Yang and Isaac Yellan and Hong Zheng and Georgy Meshcheryakov and Giovanna Ambrosini and Antoni J. Gralak and Sachi Inukai and Judith F. Kribelbauer and Marie-Luise Plescher and Semyon Kolmykov},
journal = {Nature},
year = {2026},
month = aug,
doi = {10.1038/s41586-026-10798-9},
url = {https://doi.org/10.1038/s41586-026-10798-9},
note = {CC BY},
}
RIS
TY - JOUR
TI - An expanded codebook of human transcription factor DNA-binding specificity
AU - Arttu Jolma
AU - Kaitlin U. Laverty
AU - Ali Fathi
AU - Ally W. H. Yang
AU - Isaac Yellan
AU - Ilya E. Vorontsov
AU - Sachi Inukai
AU - Judith F. Kribelbauer
AU - Antoni J. Gralak
AU - Rozita Razavi
AU - Mihai Albu
AU - Alexander V. Brechalov
AU - Zain M. Patel
AU - Vladimir Nozdrin
AU - G. A. Meshcheryakov
AU - Andrey Buyan
AU - Ivan Kozin
AU - Sergey Abramov
AU - Alexandr Boytsov
AU - Matthew T. Weirauch
AU - Oriol Fornés
AU - Vsevolod J. Makeev
AU - Jan Grau
AU - Ivo Große
AU - Philipp Bucher
AU - Bart Deplancke
AU - Ivan V. Kulakovskiy
AU - Timothy P. Hughes
AU - Philipp Bucher
AU - Bart Deplancke
AU - Oriol Fornés
AU - Jan Grau
AU - Ivo Grosse
AU - Timothy R. Hughes
AU - Arttu Jolma
AU - Fedor A. Kolpakov
AU - Ivan V. Kulakovskiy
AU - Vsevolod J. Makeev
AU - Mihai Albu
AU - Marjan Barazandeh
AU - Alexander Brechalov
AU - Zhenfeng Deng
AU - Ali Fathi
AU - Chun Hu
AU - Samuel A. Lambert
AU - Kaitlin U. Laverty
AU - Zain M. Patel
AU - Sara E. Pour
AU - Rozita Razavi
AU - Mikhail Salnikov
AU - Ally W. H. Yang
AU - Isaac Yellan
AU - Hong Zheng
AU - Georgy Meshcheryakov
AU - Giovanna Ambrosini
AU - Antoni J. Gralak
AU - Sachi Inukai
AU - Judith F. Kribelbauer
AU - Marie-Luise Plescher
AU - Semyon Kolmykov
PY - 2026
DA - 2026/08/05
JO - Nature
DO - 10.1038/s41586-026-10798-9
UR - https://doi.org/10.1038/s41586-026-10798-9
AB - 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.
SN - 0028-0836
SN - 1476-4687
ER -