Inhibition of MLL1 histone methyltransferase brings the developmental clock back to naïve pluripotency.

Embryonic stem cells (ESCs) and the post-implantation epiblast stem cells (EpiSCs) portray two different states of pluripotency. They differ with respect to epigenetic signatures, dependency of growth factor signaling circuit and cell morphology. They are interconvertible, however, with poor reconversion efficiency. This is indicative of existence of other unknown regulatory pathways govern developmental stage transition. Zhang and colleagues have recently demonstrated that pharmacological inhibition of MLL1 histone methyltransferase is casually linked to efficient reprogramming of EpiSCs to developmentally competent ESCs. MLL1 controlled H3K4me1 serves as an epigenetic valve that ensures maintenance of EpiSCs. Removing this barrier leads to global redistribution of H3K4me1 at enhancers and target gene promoters, in turn represses EpiSC specific genes and reactivates ESC specific transcriptional network. This study underscores the critical role of MLL1 in establishing discrete chromatin states indispensible for early mammalian developmental events.