Cell Stem Cell
Volume 18, Issue 4, 7 April 2016, Pages 481-494
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Article
MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency

https://doi.org/10.1016/j.stem.2016.02.004Get rights and content
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Highlights

  • MLL1 inhibition by MM-401 promotes reversion of EpiSCs to naive pluripotency

  • MLL1 controls the rate-limiting step in EpiSC reprogramming

  • An MLL1-dependent gene network is identified in pluripotent stem cells

  • Epigenetic perturbation is sufficient to initiate EpiSC-to-ESC reversion

Summary

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.

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Present address: École Polytechnique Fédérale de Lausanne, Route Cantonale, 1015 Lausanne, Switzerland