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Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation

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Title: Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation
Authors: Tomaz, RA
Harman, JL
Karimlou, D
Weavers, L
Fritsch, L
Bou-Kheir, T
Bell, E
Del Valle Torres, I
Niakan, KK
Fisher, C
Joshi, O
Stunnenberg, HG
Curry, E
Ait-Si-Ali, S
Jorgensen, HF
Azuara, V
Item Type: Journal Article
Abstract: Jmjd2/Kdm4 H3K9-demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we uncover that Jmjd2c facilitates this process by stabilizing the assembly of Mediator-Cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, while Jmjd2c-knockout ESCs remain capable of forming extra-embryonic endoderm derivatives. Dissection of the underlying molecular basis revealed that Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming for differentiation. Interestingly, Jmjd2c-bound enhancers are co-occupied by the H3K9-methyltransferase G9a/Ehmt2, independently of its H3K9-modifying activity. Loss of Jmjd2c abrogates G9a recruitment and furthermore destabilizes loading of the Mediator and Cohesin components Med1 and Smc1a at newly activated and poised enhancers in ESC-derived epiblast-like cells. These findings unveil Jmjd2c-G9a as novel enhancer-associated factors, and implicate Jmjd2c as a molecular scaffold for the assembly of essential enhancer-protein complexes with impact on timely gene activation.
Issue Date: 13-Jan-2017
Date of Acceptance: 15-Dec-2016
URI: http://hdl.handle.net/10044/1/43506
DOI: https://dx.doi.org/10.1242/dev.142489
ISSN: 0950-1991
Publisher: The Company Of Biologists Ltd
Start Page: 567
End Page: 579
Journal / Book Title: Development
Volume: 144
Issue: 4
Copyright Statement: © 2017. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Sponsor/Funder: Genesis Research Trust
Parkinson's UK
Genesis Research Trust
Genesis Research Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Genesis Research Trust
Genesis Research Trust
Genesis Research Trust
Funder's Grant Number: N/A
4045
N/A
n/a
BB/G011117/1
01032
01033
1064
Keywords: Science & Technology
Life Sciences & Biomedicine
Developmental Biology
Jmjd2c (Kdm4c)
Enhancers
Gene regulation
Embryonic stem cells
Epiblast stem cells
Lineage specification
GROUND-STATE PLURIPOTENCY
9 METHYLTRANSFERASES G9A
MOUSE EMBRYOS
HISTONE H3
SELF-RENEWAL
CPG ISLANDS
XEN CELLS
TRANSCRIPTION FACTORS
DEMETHYLASE ACTIVITY
VISCERAL ENDODERM
Jmjd2c/Kdm4c, enhancers, gene regulation, embryonic stem cells, epiblast stem cells, lineage specification
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Article Number: DEVELOP-2016-142489
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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