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Peer-reviewedCC BYNature Methods

GHT-SELEX demonstrates unexpectedly high intrinsic sequence specificity and complex DNA binding of many human transcription factors

  • Arttu Jolma1,2
  • Aldo Hernández-Corchado3,4,5,6
  • Ally W. H. Yang7,2
  • Ali Fathi8,9
  • Kaitlin U. Laverty10,7,2,11
  • Alexander V. Brechalov7,2
  • Rozita Razavi7,2
  • Mihai Albu7,2
  • Hong Zheng7,2
  • Philipp Bücher12,13,14
  • Bart Deplancke15,12,5,6
  • Oriol Fornés16,9,2
39 more authors
  • Jan Grau17
  • Ivo Große17
  • Fedor A. Kolpakov18,19
  • Vsevolod J. Makeev20
  • Marjan Barazandeh7
  • Zhenfeng Deng7
  • Chun Hu7
  • Samuel A. Lambert7
  • Zain M. Patel7
  • Sara E. Pour7
  • Mikhail Salnikov7
  • Isaac Yellan7
  • Georgy Meshcheryakov21
  • Giovanna Ambrosini22,23
  • Antoni J. Gralak15,12
  • Sachi Inukai24
  • Judith F. Kribelbauer-Swietek15,12
  • Marie-Luise Plescher17
  • Semyon K. Kolmykov19
  • Ivan Yevshin25
  • Nikita Gryzunov21
  • Ivan Kozin26,21,20
  • Mikhail Nikonov26
  • Vladimir Nozdrin26
  • Arsenii O. Zinkevich26
  • Kateřina Faltejsková27,28
  • Pavel Kravchenko29
  • Sergey Abramov30,20
  • Alexandr Boytsov30,20
  • Vasilii Kamenets20
  • Dmitry Penzar20
  • Anton Vlasov31
  • Ilya E. Vorontsov20
  • Quaid Morris10
  • Xiaoting Chen32
  • Matthew T. Weirauch32
  • Ivan V. Kulakovskiy33,21,20
  • Hamed Shateri Najafabadi34,35
  • Timothy Hughes36,37
37 affiliations
  1. 1Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. [email protected]
  2. 2Donnelly Centre, University of Toronto, Toronto, ON M5S 3E, Canada
  3. 3Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  4. 4Victor P. Dahdaleh Institute of Genomic Medicine, Montreal, Quebec, Canada
  5. 5Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada
  6. 6Victor P. Dahdaleh Institute of Genomic Medicine, Montréal, QC HA 0G1, Canada
  7. 7Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
  8. 8Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  9. 9Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
  10. 10Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  11. 11Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 1006, USA
  12. 12Swiss Institute of Bioinformatics, Lausanne, Switzerland
  13. 13Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, Moscow, Russia
  14. 14Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991, Moscow, Russia and Institute of Protein Research, Russian Academy of Sciences, 142290, Pushchino, Russia
  15. 15Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
  16. 16Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
  17. 17Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle, Germany
  18. 18Bioinformatics Laboratory, Federal Research Center for Information and Computational Technologies, Novosibirsk, Russia
  19. 19Department of Computational Biology, Sirius University of Science and Technology, Sirius, Russia
  20. 20Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
  21. 21Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia
  22. 22Bioinformatics Competence Center, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
  23. 23Bioinformatics Competence Center, Université de Lausanne, Lausanne, Switzerland
  24. 24Chugai Pharmaceutical Co. Ltd, Tokyo, Japan
  25. 25Biosoft.Ru LLC, Novosibirsk, Russia
  26. 26Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
  27. 27Computer Science Institute, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic
  28. 28Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
  29. 29Max Planck Institute of Biochemistry, Planegg, Germany
  30. 30Altius Institute for Biomedical Sciences, Seattle, WA, USA
  31. 31Center for Molecular and Cellular Bioengineering (CMCB), TUD Dresden University of Technology, Biotechnologisches Zentrum (BIOTEC), Dresden, Germany
  32. 32Cincinnati Children’s Hospital, Cincinnati, OH, USA
  33. 33Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, Ufa, Russia
  34. 34Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [email protected]
  35. 35Victor P. Dahdaleh Institute of Genomic Medicine, Montreal, Quebec, Canada. [email protected]
  36. 36Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [email protected]
  37. 37Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. [email protected]
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Abstract

There is ongoing debate regarding the degree to which transcription factors (TFs) independently specify genomic binding: TF binding motifs are typically short and degenerate, yielding many more binding site predictions than observed in cells. Here we present genomic high-throughput SELEX (GHT-SELEX)—a scalable method that surveys intrinsic binding of purified TFs to the fragmented, naked and unmodified genome. GHT-SELEX peaks for 179 diverse human TFs display surprisingly high overlap with chromatin immunoprecipitation sequencing peaks for the same TF. Comparable overlap can be obtained from motifs using appropriate analytical approaches. For C2H2 zinc finger (zf) proteins—the largest class of human TFs—GHT-SELEX shows that modular, alternative engagement of C2H2-zf domains is the norm, enabling several types of distinct target sites, and frequently involving internal duplication and divergence within the C2H2-zf array. Altogether, it is common for TFs to delineate a large fraction of in vivo genomic binding sites independently of other cellular factors.

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Cite

BibTeXRIS
BibTeX
@article{jolma2026ghtselex,
  title = {{GHT-SELEX demonstrates unexpectedly high intrinsic sequence specificity and complex DNA binding of many human transcription factors}},
  author = {Arttu Jolma and Aldo Hernández-Corchado and Ally W. H. Yang and Ali Fathi and Kaitlin U. Laverty and Alexander V. Brechalov and Rozita Razavi and Mihai Albu and Hong Zheng and Philipp Bücher and Bart Deplancke and Oriol Fornés and Jan Grau and Ivo Große and Fedor A. Kolpakov and Vsevolod J. Makeev and Marjan Barazandeh and Zhenfeng Deng and Chun Hu and Samuel A. Lambert and Zain M. Patel and Sara E. Pour and Mikhail Salnikov and Isaac Yellan 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 Ilya E. Vorontsov and Quaid Morris and Xiaoting Chen and Matthew T. Weirauch and Ivan V. Kulakovskiy and Hamed Shateri Najafabadi and Timothy Hughes},
  journal = {Nature Methods},
  year = {2026},
  month = aug,
  doi = {10.1038/s41592-026-03177-9},
  url = {https://doi.org/10.1038/s41592-026-03177-9},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - GHT-SELEX demonstrates unexpectedly high intrinsic sequence specificity and complex DNA binding of many human transcription factors
AU  - Arttu Jolma
AU  - Aldo Hernández-Corchado
AU  - Ally W. H. Yang
AU  - Ali Fathi
AU  - Kaitlin U. Laverty
AU  - Alexander V. Brechalov
AU  - Rozita Razavi
AU  - Mihai Albu
AU  - Hong Zheng
AU  - Philipp Bücher
AU  - Bart Deplancke
AU  - Oriol Fornés
AU  - Jan Grau
AU  - Ivo Große
AU  - Fedor A. Kolpakov
AU  - Vsevolod J. Makeev
AU  - Marjan Barazandeh
AU  - Zhenfeng Deng
AU  - Chun Hu
AU  - Samuel A. Lambert
AU  - Zain M. Patel
AU  - Sara E. Pour
AU  - Mikhail Salnikov
AU  - Isaac Yellan
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  - Ilya E. Vorontsov
AU  - Quaid Morris
AU  - Xiaoting Chen
AU  - Matthew T. Weirauch
AU  - Ivan V. Kulakovskiy
AU  - Hamed Shateri Najafabadi
AU  - Timothy Hughes
PY  - 2026
DA  - 2026/08/05
JO  - Nature Methods
DO  - 10.1038/s41592-026-03177-9
UR  - https://doi.org/10.1038/s41592-026-03177-9
AB  - There is ongoing debate regarding the degree to which transcription factors (TFs) independently specify genomic binding: TF binding motifs are typically short and degenerate, yielding many more binding site predictions than observed in cells. Here we present genomic high-throughput SELEX (GHT-SELEX)—a scalable method that surveys intrinsic binding of purified TFs to the fragmented, naked and unmodified genome. GHT-SELEX peaks for 179 diverse human TFs display surprisingly high overlap with chromatin immunoprecipitation sequencing peaks for the same TF. Comparable overlap can be obtained from motifs using appropriate analytical approaches. For C2H2 zinc finger (zf) proteins—the largest class of human TFs—GHT-SELEX shows that modular, alternative engagement of C2H2-zf domains is the norm, enabling several types of distinct target sites, and frequently involving internal duplication and divergence within the C2H2-zf array. Altogether, it is common for TFs to delineate a large fraction of in vivo genomic binding sites independently of other cellular factors.
SN  - 1548-7091
SN  - 1548-7105
ER  -