Peer-reviewedCC BYNature Communications
Extensive binding of poorly characterized human transcription factors to genomic dark matter
25 affiliations
- 1Donnelly Centre and Department of Molecular Genetics, Toronto, ON, Canada
- 2Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- 3Victor P. Dahdaleh Institute of Genomic Medicine, Montréal, QC, Canada
- 4Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
- 5Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- 6Swiss Institute of Bioinformatics, Lausanne, Switzerland
- 7Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
- 8Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle, Germany
- 9Bioinformatics Laboratory, Federal Research Center for Information and Computational Technologies, Novosibirsk, Russia
- 10Department of Computational Biology, Sirius University of Science and Technology, Sirius, Russia
- 11Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia
- 12Bioinformatics Competence Center, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- 13Bioinformatics Competence Center, Université de Lausanne, Lausanne, Switzerland
- 14Chugai Pharmaceutical Co., Ltd, Tokyo, Japan
- 15Biosoft.Ru LLC, Novosibirsk, Russia
- 16Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
- 17Computer Science Institute, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic
- 18Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
- 19Max Planck Institute of Biochemistry, Planegg, Germany
- 20Altius Institute for Biomedical Sciences, Seattle, WA, USA
- 21Biotechnologisches Zentrum (BIOTEC), Center for Molecular and Cellular Bioengineering (CMCB), TUD Dresden University of Technology, Dresden, Germany
- 22Cincinnati Children’s Hospital, Cincinnati, OH, USA
- 23Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, Ufa, Russia
- 24Department of Human Genetics, McGill University, Montréal, QC, Canada
- 25Donnelly Centre and Department of Molecular Genetics, Toronto, ON, Canada. [email protected]
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.
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BibTeX
@article{razavi2026extensive,
title = {{Extensive binding of poorly characterized human transcription factors to genomic dark matter}},
author = {Rozita Razavi and Ali Fathi and Isaac Yellan and Alexander V. Brechalov and Kaitlin U. Laverty and Arttu Jolma and Aldo Hernández-Corchado and Hong Zheng and Ally W. H. Yang and Mihai Albu and Marjan Barazandeh and Chun Hu and Ilya E. Vorontsov and Zain M. Patel and Bart Deplancke and Oriol Fornés and Jan Grau and Ivo Große and Fedor A. Kolpakov and Vsevolod J. Makeev and Zhenfeng Deng and Samuel A. Lambert and Sara E. Pour and Mikhail Salnikov and Georgy Meshcheryakov and Giovanna Ambrosini and Antoni J. Gralak and Sachi Inukai and Judith F. Kribelbauer-Swietek and Marie-Luise Plescher and Semyon K. Kolmykov and Ivan Yevshin and Nikita Gryzunov and Ivan Kozin and Mikhail Nikonov and Vladimir Nozdrin and Arsenii O. Zinkevich and Kateřina Faltejsková and Pavel Kravchenko and Sergey Abramov and Alexandr Boytsov and Vasilii Kamenets and Dmitry Penzar and Anton Vlasov and Xiaoting Chen and Matthew T. Weirauch and Ivan V. Kulakovskiy and Philipp Bücher and Quaid Morris and Hamed Shateri Najafabadi and Timothy R. Hughes},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-75376-z},
url = {https://doi.org/10.1038/s41467-026-75376-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - Extensive binding of poorly characterized human transcription factors to genomic dark matter
AU - Rozita Razavi
AU - Ali Fathi
AU - Isaac Yellan
AU - Alexander V. Brechalov
AU - Kaitlin U. Laverty
AU - Arttu Jolma
AU - Aldo Hernández-Corchado
AU - Hong Zheng
AU - Ally W. H. Yang
AU - Mihai Albu
AU - Marjan Barazandeh
AU - Chun Hu
AU - Ilya E. Vorontsov
AU - Zain M. Patel
AU - Bart Deplancke
AU - Oriol Fornés
AU - Jan Grau
AU - Ivo Große
AU - Fedor A. Kolpakov
AU - Vsevolod J. Makeev
AU - Zhenfeng Deng
AU - Samuel A. Lambert
AU - Sara E. Pour
AU - Mikhail Salnikov
AU - Georgy Meshcheryakov
AU - Giovanna Ambrosini
AU - Antoni J. Gralak
AU - Sachi Inukai
AU - Judith F. Kribelbauer-Swietek
AU - Marie-Luise Plescher
AU - Semyon K. Kolmykov
AU - Ivan Yevshin
AU - Nikita Gryzunov
AU - Ivan Kozin
AU - Mikhail Nikonov
AU - Vladimir Nozdrin
AU - Arsenii O. Zinkevich
AU - Kateřina Faltejsková
AU - Pavel Kravchenko
AU - Sergey Abramov
AU - Alexandr Boytsov
AU - Vasilii Kamenets
AU - Dmitry Penzar
AU - Anton Vlasov
AU - Xiaoting Chen
AU - Matthew T. Weirauch
AU - Ivan V. Kulakovskiy
AU - Philipp Bücher
AU - Quaid Morris
AU - Hamed Shateri Najafabadi
AU - Timothy R. Hughes
PY - 2026
DA - 2026/08/05
JO - Nature Communications
DO - 10.1038/s41467-026-75376-z
UR - https://doi.org/10.1038/s41467-026-75376-z
AB - 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.
SN - 2041-1723
ER -