Nucleosome fibre topology guides transcription factor binding to enhancers (2024)

O'Dwyer, M. R., Azagury, M., Furlong, K., Alsheikh, A., Hall-Ponsele, E., Pinto, H., Fyodorov, D. V., Jaber, M., Papachristoforou, E., Benchetrit, H., Ashmore, J., Makedonski, K., Rahamim, M., Hanzevacki, M., Yassen, H., Skoda, S., Levy, A., Pollard, S. M., Skoultchi, A. I., ... Soufi, A. (Accepted/In press). Nucleosome fibre topology guides transcription factor binding to enhancers. Nature.

O'Dwyer, Michael R. ; Azagury, Meir ; Furlong, Katharine et al. / Nucleosome fibre topology guides transcription factor binding to enhancers. In: Nature. 2024.

@article{57fa8639f5a14c319433d0143ed4dd38,

title = "Nucleosome fibre topology guides transcription factor binding to enhancers",

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 enhancers. 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 nucleosome resolution. We show that motif recognition on mono-nucleosomes can only decipher 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 act as signpost elements, directing TF combinatorial binding to enhancers. ",

author = "O'Dwyer, {Michael R.} and Meir Azagury and Katharine Furlong and Amani Alsheikh and Elisa Hall-Ponsele and Hugo Pinto and Fyodorov, {Dmitry V.} and Mohammad Jaber and Eleni Papachristoforou and Hana Benchetrit and James Ashmore and Kirill Makedonski and Moran Rahamim and Marta Hanzevacki and Hazar Yassen and Samuel Skoda and Adi Levy and Pollard, {Steven M.} and Skoultchi, {Arthur I} and Yosef Buganim and Abdenour Soufi",

note = "We thank Prof I. Chambers, and Dr R. Illingworth for comments on the manuscript and insightful discussions. We thank Prof Keisuke Kaji for providing the secondary reprogrammable TNG-KOSM-MEFs and insightful discussions. ",

year = "2024",

month = nov,

day = "1",

language = "English",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

}

O'Dwyer, MR, Azagury, M, Furlong, K, Alsheikh, A, Hall-Ponsele, E, Pinto, H, Fyodorov, DV, Jaber, M, Papachristoforou, E, Benchetrit, H, Ashmore, J, Makedonski, K, Rahamim, M, Hanzevacki, M, Yassen, H, Skoda, S, Levy, A, Pollard, SM, Skoultchi, AI, Buganim, Y 2024, 'Nucleosome fibre topology guides transcription factor binding to enhancers', Nature.

Nucleosome fibre topology guides transcription factor binding to enhancers. / O'Dwyer, Michael R.; Azagury, Meir; Furlong, Katharine et al.
In: Nature, 01.11.2024.

Research output: Contribution to journal › Article › peer-review

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 - We thank Prof I. Chambers, and Dr R. Illingworth for comments on the manuscript and insightful discussions. We thank Prof Keisuke Kaji for providing the secondary reprogrammable TNG-KOSM-MEFs and insightful discussions.

PY - 2024/11/1

Y1 - 2024/11/1

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 enhancers. 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 nucleosome resolution. We show that motif recognition on mono-nucleosomes can only decipher 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 act 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 enhancers. 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 nucleosome resolution. We show that motif recognition on mono-nucleosomes can only decipher 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 act as signpost elements, directing TF combinatorial binding to enhancers.

UR - https://git.ecdf.ed.ac.uk/soufi_lab/motif_mononucleosome

UR - https://git.ecdf.ed.ac.uk/soufi_lab/motif_nucleosome_arrays/-/blob/main/README.md?ref_type=heads

M3 - Article

SN - 0028-0836

JO - Nature

JF - Nature

ER -

O'Dwyer MR, Azagury M, Furlong K, Alsheikh A, Hall-Ponsele E, Pinto H et al. Nucleosome fibre topology guides transcription factor binding to enhancers. Nature. 2024 Nov 1.