Nucleosome fibre topology guides transcription factor binding to enhancers

• 成果类型: Article
• 署名作者: O'Dwyer, Michael R.; Azagury, Meir; Furlong, Katharine; Alsheikh, Amani; Hall-Ponsele, Elisa; Pinto, Hugo; Fyodorov, Dmitry V.; Jaber, Mohammad; Papachristoforou, Eleni; Benchetrit, Hana; Ashmore, James; Makedonski, Kirill; Rahamim, Moran; Hanzevacki, Marta; Yassen, Hazar; Skoda, Samuel; Levy, Adi; Pollard, Steven M.; Skoultchi, Arthur I.; Buganim, Yosef; Soufi, Abdenour
• 署名单位: University of Edinburgh; University of Edinburgh; Hebrew University of Jerusalem; University of Edinburgh; King Abdulaziz City for Science & Technology; Yeshiva University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1299
• DOI: 10.1038/s41586-024-08333-9
• 发表日期: 2025-02-01
• 页码: 251-+
• 关键词: trophoblast stem-cells; direct conversion; direct induction; dna; chromatin; fibroblasts; mechanisms; expression; occupancy; meme

摘要

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(1). 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.