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DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency

Lookup NU author(s): Dr Ruchi ShuklaORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019 The Authors. The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in two small molecule inhibitors (2i) results in redistribution of polycomb (H3K27me3) away from its target loci. Here, we demonstrate that 3D genome organization is also altered in 2i, with chromatin decompaction at polycomb target loci and a loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground state, we are able to restore to ESC in 2i the H3K27me3 distribution, as well as polycomb-mediated 3D genome organization that is characteristic of primed ESCs grown in serum. However, these cells retain the functional characteristics of 2i ground-state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organization but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.© 2019 The AuthorsMcLaughlin et al. demonstrate that the global DNA methylation state directs the PRC-dependent 3D organization of mouse ESCs and probably early blastocysts. Their findings highlight a central role for DNA methylation and its influence on polycomb, in shaping major aspects of 3D genome organization in stem cells.

Publication metadata

Author(s): McLaughlin K, Flyamer IM, Thomson JP, Mjoseng HK, Shukla R, Williamson I, Grimes GR, Illingworth RS, Adams IR, Pennings S, Meehan RR, Bickmore WA

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2019

Volume: 29

Issue: 7

Pages: 1974-1985.e6

Print publication date: 12/11/2019

Online publication date: 12/11/2019

Acceptance date: 09/10/2019

Date deposited: 05/02/2020

ISSN (electronic): 2211-1247

Publisher: Cell Press


DOI: 10.1016/j.celrep.2019.10.031


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