Nucleosome fibre topology guides transcription factor binding to enhancers

Michael R. O’Dwyer, Meir Azagury, Katharine Furlong, Amani Alsheikh, Elisa Hall-Ponsele, Hugo Pinto, Dmitry V. Fyodorov, Mohammad Jaber, Eleni Papachristoforou, Hana Benchetrit, James Ashmore, Kirill Makedonski, Moran Rahamim, Marta Hanzevacki, Hazar Yassen, Samuel Skoda, Adi Levy, Steven M. Pollard, Arthur I. Skoultchi, Yosef Buganim () and Abdenour Soufi ()
Additional contact information
Michael R. O’Dwyer: University of Edinburgh
Meir Azagury: The Hebrew University-Hadassah Medical School
Katharine Furlong: University of Edinburgh
Amani Alsheikh: University of Edinburgh
Elisa Hall-Ponsele: University of Edinburgh
Hugo Pinto: Albert Einstein College of Medicine
Dmitry V. Fyodorov: Albert Einstein College of Medicine
Mohammad Jaber: The Hebrew University-Hadassah Medical School
Eleni Papachristoforou: University of Edinburgh
Hana Benchetrit: The Hebrew University-Hadassah Medical School
James Ashmore: University of Edinburgh
Kirill Makedonski: The Hebrew University-Hadassah Medical School
Moran Rahamim: The Hebrew University-Hadassah Medical School
Marta Hanzevacki: University of Edinburgh
Hazar Yassen: The Hebrew University-Hadassah Medical School
Samuel Skoda: University of Edinburgh
Adi Levy: The Hebrew University-Hadassah Medical School
Steven M. Pollard: University of Edinburgh
Arthur I. Skoultchi: Albert Einstein College of Medicine
Yosef Buganim: The Hebrew University-Hadassah Medical School
Abdenour Soufi: University of Edinburgh

Nature, 2025, vol. 638, issue 8049, 251-260

Abstract: Abstract 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 enhancers1. 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.

Date: 2025
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DOI: 10.1038/s41586-024-08333-9

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