Nucleosome fibre topology guides transcription factor binding to enhancers
Cellular identity requires the concerted action of multiple transcription factors (TFs) bound together to enhancers of cell-type-specific genes. Despite TFs recognizing specific DNA motifs within accessible chromatin, this information is insufficient to explain how TFs select enhancers<sup>1</sup>. Here we compared four different TF combinations that induce different cell states, analysing TF genome occupancy, chromatin accessibility, nucleosome positioning and 3D genome organization at the nucleosome resolution. We show that motif recognition on mononucleosomes can decipher only the individual binding of TFs. When bound together, TFs act cooperatively or competitively to target nucleosome arrays with defined 3D organization, displaying motifs in particular patterns. In one combination, motif directionality funnels TF combinatorial binding along chromatin loops, before infiltrating laterally to adjacent enhancers. In other combinations, TFs assemble on motif-dense and highly interconnected loop junctions, and subsequently translocate to nearby lineage-specific sites. We propose a guided-search model in which motif grammar on nucleosome fibres acts as signpost elements, directing TF combinatorial binding to enhancers.
Authors
- Yosef Buganim
- Michael O’Dwyer (ORCID: https://orcid.org/0000-0002-1371-1421)
- Kirill Makedonski
- Abdenour Soufi (ORCID: https://orcid.org/0000-0002-3666-3266)
- Meir Azagury
- Steven M. Pollard (ORCID: https://orcid.org/0000-0001-6428-0492)
- Eleni Papachristoforou (ORCID: https://orcid.org/0000-0003-1553-1405)
- Hazar Yassen
- Hana Benchetrit
- Dmitry V. Fyodorov (ORCID: https://orcid.org/0000-0002-3080-1787)
- Elisa Hall-Ponselé
- James Ashmore
- Moran Rahamim
- Hugo Pinto (ORCID: https://orcid.org/0000-0002-6970-4693)
- Arthur I. Skoultchi (ORCID: https://orcid.org/0000-0001-5096-8077)
- Mohammad Jaber (ORCID: https://orcid.org/0000-0002-3859-7071)
- Adi Levy
- Marta Hanzevacki
- Samuel Skoda
- Katharine Furlong
- Amani Alsheikh
Institutions
- King Abdulaziz City for Science and Technology (SA)
- Albert Einstein College of Medicine (US)
- Hebrew University of Jerusalem (IL)
- Hadassah Medical Center (IL)
- Edinburgh Cancer Research (GB)
- MRC Centre for Regenerative Medicine (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1038/s41586-024-08333-9
- Citations
- 25
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 5.85
Funders
- Israel Cancer Research Fund
- Oregon Health and Science University
- Cancer Research UK
- Israel Science Foundation
- King Abdulaziz City for Science and Technology
- LEO Fondet
- Darwin Trust of Edinburgh
- National Institutes of Health
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council
- Natural Environment Research Council