Integrative Proteomic Profiling Reveals PRC2-Dependent Epigenetic Crosstalk Maintains Ground-State Pluripotency

Cell Stem Cell. 2019 Jan 3;24(1):123-137.e8. doi: 10.1016/j.stem.2018.10.017. Epub 2018 Nov 21.


The pluripotent ground state is defined as a basal state free of epigenetic restrictions, which influence lineage specification. While naive embryonic stem cells (ESCs) can be maintained in a hypomethylated state with open chromatin when grown using two small-molecule inhibitors (2i)/leukemia inhibitory factor (LIF), in contrast to serum/LIF-grown ESCs that resemble early post-implantation embryos, broader features of the ground-state pluripotent epigenome are not well understood. We identified epigenetic features of mouse ESCs cultured using 2i/LIF or serum/LIF by proteomic profiling of chromatin-associated complexes and histone modifications. Polycomb-repressive complex 2 (PRC2) and its product H3K27me3 are highly abundant in 2i/LIF ESCs, and H3K27me3 is distributed genome-wide in a CpG-dependent fashion. Consistently, PRC2-deficient ESCs showed increased DNA methylation at sites normally occupied by H3K27me3 and increased H4 acetylation. Inhibiting DNA methylation in PRC2-deficient ESCs did not affect their viability or transcriptome. Our findings suggest a unique H3K27me3 configuration protects naive ESCs from lineage priming, and they reveal widespread epigenetic crosstalk in ground-state pluripotency.

Keywords: H3K27me3; chromatin profiling; embryonic stem cells; epigenetics; ground-state pluripotency; histone modifications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Histones / genetics
  • Histones / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism*
  • Protein Processing, Post-Translational
  • Proteome / analysis*


  • Chromatin
  • Histones
  • Proteome
  • Polycomb Repressive Complex 2