TY - JOUR
T1 - Nucleosome fibre topology guides transcription factor binding to enhancers
AU - O’Dwyer, Michael R.
AU - Azagury, Meir
AU - Furlong, Katharine
AU - Alsheikh, Amani
AU - Hall-Ponsele, Elisa
AU - Pinto, Hugo
AU - Fyodorov, Dmitry V.
AU - Jaber, Mohammad
AU - Papachristoforou, Eleni
AU - Benchetrit, Hana
AU - Ashmore, James
AU - Makedonski, Kirill
AU - Rahamim, Moran
AU - Hanzevacki, Marta
AU - Yassen, Hazar
AU - Skoda, Samuel
AU - Levy, Adi
AU - Pollard, Steven M.
AU - Skoultchi, Arthur I.
AU - Buganim, Yosef
AU - Soufi, Abdenour
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85212439527&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-08333-9
DO - 10.1038/s41586-024-08333-9
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C2 - 39695228
AN - SCOPUS:85212439527
SN - 0028-0836
JO - Nature
JF - Nature
M1 - 11485
ER -