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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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Tomaz, RA 
Harman, JL 
Karimlou, D 
Weavers, L 
Fritsch, L 


Jmjd2 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 reveal that Jmjd2c facilitates this process by stabilising 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 (also known as Ehmt2), independently of its H3K9-modifying activity. Loss of Jmjd2c abrogates G9a recruitment and further destabilises 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 and G9a as novel enhancer-associated factors, and implicate Jmjd2c as a molecular scaffold for the assembly of essential enhancer-protein complexes with an impact on timely gene activation.



Jmjd2c (Kdm4c), Enhancers, Gene regulation, Embryonic stem cells, Epiblast stem cells, Lineage specification

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Company of Biologists
British Heart Foundation (FS/15/38/31516)
British Heart Foundation (None)
This work was supported by the Fundação para a Ciência e a Tecnologia (Portugal) (SFRH/BD/70242/2010), by the Genesis Research Trust (P55000), by the British Heart Foundation (PG/12/86/29930), by an Imperial College London President's PhD Scholarship (STU0082882), by the Centre National de la Recherche Scientifique, by the Medical Research Council (MR/K00090X/1 and MR/K500793/1), by the Wellcome Trust Sanger Institute, by the Francis Crick Institute [which receives its core funding from Cancer Research UK (FC001120), the UK Medical Research Council (FC001120) and the Wellcome Trust (FC001120)], by a European Research Council grant (ERC-2013-ADG, 339431 ‘SysStemCell’) and by Imperial College London. Deposited in PMC for immediate release.