MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency


Zhang H., Gayen S., Xiong J., Zhou B., Shanmugam A. K., Sun Y., ...More

Cell Stem Cell, vol.18, no.4, pp.481-494, 2016 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 18 Issue: 4
  • Publication Date: 2016
  • Doi Number: 10.1016/j.stem.2016.02.004
  • Journal Name: Cell Stem Cell
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.481-494
  • 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.
  • Istanbul Medipol University Affiliated: Yes

Abstract

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.