DNA-guided transcription factor interactions extend human gene regulatory code

Zhiyuan Xie, Ilya Sokolov, Maria Osmala, Xue Yue, Grace Bower, J. Patrick Pett, Yinan Chen, Kai Wang, Ayse Derya Cavga, Alexander Popov, Sarah A. Teichmann, Ekaterina Morgunova, Evgeny Z. Kvon, Yimeng Yin () and Jussi Taipale ()
Additional contact information
Zhiyuan Xie: Tongji University
Ilya Sokolov: University of Cambridge
Maria Osmala: University of Helsinki
Xue Yue: Tongji University
Grace Bower: University of California, Irvine
J. Patrick Pett: Wellcome Sanger Institute
Yinan Chen: University of Cambridge
Kai Wang: Tongji University
Ayse Derya Cavga: University of Cambridge
Alexander Popov: European Synchrotron Radiation Facility (ESRF)
Sarah A. Teichmann: University of Cambridge
Ekaterina Morgunova: Karolinska Institutet
Evgeny Z. Kvon: University of California, Irvine
Yimeng Yin: Tongji University
Jussi Taipale: University of Cambridge

Nature, 2025, vol. 641, issue 8065, 1329-1338

Abstract: Abstract In the same way that the mRNA-binding specificities of transfer RNAs define the genetic code, the DNA-binding specificities of transcription factors (TFs) form the molecular basis of the gene regulatory code1,2. The human gene regulatory code is much more complex than the genetic code, in particular because there are more than 1,600 TFs that commonly interact with each other. TF–TF interactions are required for specifying cell fate and executing cell-type-specific transcriptional programs. Despite this, the landscape of interactions between DNA-bound TFs is poorly defined. Here we map the biochemical interactions between DNA-bound TFs using CAP-SELEX, a method that can simultaneously identify individual TF binding preferences, TF–TF interactions and the DNA sequences that are bound by the interacting complexes. A screen of more than 58,000 TF–TF pairs identified 2,198 interacting TF pairs, 1,329 of which preferentially bound to their motifs arranged in a distinct spacing and/or orientation. We also discovered 1,131 TF–TF composite motifs that were markedly different from the motifs of the individual TFs. In total, we estimate that the screen identified between 18% and 47% of all human TF–TF motifs. The novel composite motifs we found were enriched in cell-type-specific elements, active in vivo and more likely to be formed between developmentally co-expressed TFs. Furthermore, TFs that define embryonic axes commonly interacted with different TFs and bound to distinct motifs, explaining how TFs with a similar specificity can define distinct cell types along developmental axes.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08844-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:641:y:2025:i:8065:d:10.1038_s41586-025-08844-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08844-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().