Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency

Emma Bell, Edward W. Curry, Wout Megchelenbrink, Luc Jouneau, Vincent Brochard, Rute A. Tomaz, King Hang T. Mau, Yaser Atlasi, Roshni A. de Souza, Hendrik Marks, Hendrik G. Stunnenberg, Alice Jouneau () and Véronique Azuara ()
Additional contact information
Emma Bell: Imperial College London, Hammersmith Hospital
Edward W. Curry: Imperial College London, Hammersmith Hospital
Wout Megchelenbrink: Radboud University, Faculty of Science, Department of Molecular Biology
Luc Jouneau: Université Paris-Saclay, INRAE, ENVA, BREED, Domaine de Vilvert, bat 230
Vincent Brochard: Université Paris-Saclay, INRAE, ENVA, BREED, Domaine de Vilvert, bat 230
Rute A. Tomaz: Imperial College London, Hammersmith Hospital
King Hang T. Mau: Imperial College London, Hammersmith Hospital
Yaser Atlasi: Radboud University, Faculty of Science, Department of Molecular Biology
Roshni A. de Souza: Imperial College London, Hammersmith Hospital
Hendrik Marks: Radboud University, Faculty of Science, Department of Molecular Biology
Hendrik G. Stunnenberg: Radboud University, Faculty of Science, Department of Molecular Biology
Alice Jouneau: Université Paris-Saclay, INRAE, ENVA, BREED, Domaine de Vilvert, bat 230
Véronique Azuara: Imperial College London, Hammersmith Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Clusters of enhancers, referred as to super-enhancers (SEs), control the expression of cell identity genes. The organisation of these clusters, and how they are remodelled upon developmental transitions remain poorly understood. Here, we report the existence of two types of enhancer units within SEs typified by distinctive CpG methylation dynamics in embryonic stem cells (ESCs). We find that these units are either prone for decommissioning or remain constitutively active in epiblast stem cells (EpiSCs), as further established in the peri-implantation epiblast in vivo. Mechanistically, we show a pivotal role for ESRRB in regulating the activity of ESC-specific enhancer units and propose that the developmentally regulated silencing of ESRRB triggers the selective inactivation of these units within SEs. Our study provides insights into the molecular events that follow the loss of ESRRB binding, and offers a mechanism by which the naive pluripotency transcriptional programme can be partially reset upon embryo implantation.

Date: 2020
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DOI: 10.1038/s41467-020-14916-7

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