MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency
Keywords: The interconversion between naive and primed ; pluripotent states is accompanied by drastic epigenetic ; rearrangements. However ; it is unclear whether ; intrinsic epigenetic events can drive reprogramming ; to naive pluripotency or if distinct chromatin states ; are instead simply a reflection of discrete pluripotent ; states. Here ; we show that blocking histone H3K4 ; methyltransferase MLL1 activity with the small ; molecule ; inhibitor MM-401 reprograms mouse epiblast ; stem cells (EpiSCs) to naive pluripotency. This reversion ; is highly efficient and synchronized ; with more ; than 50% of treated EpiSCs exhibiting features of ; naive embryonic stem cells (ESCs) within 3 days. Reverted ; ESCs reactivate the silenced X chromosome ; and contribute to embryos following blastocyst injection ; generating germline ; competent chimeras. ; Importantly ; blocking MLL1 leads to global redistribution ; of H3K4me1 at enhancers and represses lineage ; determinant factors and EpiSC markers ; which ; indirectly regulate ESC transcription circuitry. These ; findings show that discrete perturbation of H3K4 ; methylation is sufficient to drive reprogramming to ; naive pluripotency.
Record created on 2016-07-19, modified on 2016-09-08