Histone demethylases have recognized roles in the control of gene expression during development and disease, and are typically associated with the remodelling of the chromatin environment. Jmjd2/Kdm4 H3K9-demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity, but their specific roles during the exit from pluripotency are still unclear. In this issue (p. 567), Véronique Azuara and colleagues uncover a previously unrecognized functional link between Jmjd2c recruitment to lineage-specific enhancers and ESC priming for differentiation. The authors show that Jmjd2c is required for the proper assembly of mediator-cohesin complexes at lineage-specific enhancer regions, and that differentiation is stalled at an early post-implantation epiblast-like stage in both Jmjd2c-knockout and Jmjd2c-knockdown ESCs. Interestingly, Jmjd2c-deficient cells were still able to differentiate towards extra-embryonic endoderm-like cells. At the chromosomal level, the authors showed how Jmjd2c-bound enhancers are co-occupied by the H3K9-methyltransferase G9a/Ehmt2 independently of its canonical H3K9-modifying activity, and suggest that Jmjd2c-G9a co-occupancy might facilitate the loading of Med1 and Smc1a molecules. This study is significant and novel as it reveals a new mechanism for the regulation of lineage priming in ESCs via Jmjd2c-mediated stabilisation of essential protein complex assembly at enhancers.
