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Activation of transcription factor circuity in 2i-induced ground state pluripotency is independent of repressive global epigenetic landscapes

Lookup NU author(s): Dr Ruchi ShuklaORCiD

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

Abstract

Mouse embryonic stem cells (mESCs) cultured with MEK/ERK and GSK3β (2i) inhibitors transition to ground state pluripotency. Gene expression changes, redistribution of histone H3K27me3 profiles and global DNA hypomethylation are hallmarks of 2i exposure, but it is unclear whether epigenetic alterations are required to achieve and maintain ground state or occur as an outcome of 2i signal induced changes. Here we show that ESCs with three epitypes, WT, constitutively methylated, or hypomethylated, all undergo comparable morphological, protein expression and transcriptome changes independently of global alterations of DNA methylation levels or changes in H3K27me3 profiles. Dazl and Fkbp6 expression are induced by 2i in all three epitypes, despite exhibiting hypermethylated promoters in constitutively methylated ESCs. We identify a number of activated gene promoters that undergo 2i dependent loss of H3K27me3 in all three epitypes, however genetic and pharmaceutical inhibition experiments show that H3K27me3 is not required for their silencing in non-2i conditions. By separating and defining their contributions, our data suggest that repressive epigenetic systems play minor roles in mESC self-renewal and naïve ground state establishment by core sets of dominant pluripotency associated transcription factor networks, which operate independently from these epigenetic processes.

Publication metadata

Author(s): Shukla R, Mjoseng HK, Thomson JP, Kling S, Sproul D, Dunican DS, Ramsahoye B, Wongtawan T, Treindl F, Templin MF, Adams IR, Pennings S, Meehan RR

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2020

Volume: 48

Issue: 14

Pages: 7748-7766

Print publication date: 20/08/2020

Online publication date: 25/06/2020

Acceptance date: 15/06/2020

Date deposited: 05/07/2020

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: https://doi.org/10.1093/nar/gkaa529

DOI: 10.1093/nar/gkaa529

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Funding

Funder referenceFunder name
Funding for open access charge: Medical Research Council.
Work in I.R.A.’s lab is supported by MRC [MC_UU_00007/6]
Work in R.R.M.’s lab is supported by Medical Research Council [MC_PC_U127574433 and MC_UU_0007/17];
Work in S.P’s lab is supported by the BBSRC and BHF;
Work in D.S.’s lab is funded by CRUK [C47648/A20837];
Work in M.T.’s lab is supported by Innovative Medicine Initiative Joint Undertaking (IMI JU) [115001] (MARCAR project);
Work in R.S.’s lab is funded by Newcastle University's Research Fellowship scheme;

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