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

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

Author information

1
Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life Sciences (RIMLS), 6525GA Nijmegen, the Netherlands.
2
Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000 Ghent, Belgium.
3
Institute of Human Genetics, CNRS-Université de Montpellier UMR 9002, 34000 Montpellier, France.
4
Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Nijmegen Medical Centre (RadboudUMC), 6525GA Nijmegen, the Netherlands.
5
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
6
Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life Sciences (RIMLS), 6525GA Nijmegen, the Netherlands; Department of Molecular Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Oncode Institute, Radboud University, Nijmegen, the Netherlands.
7
Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life Sciences (RIMLS), 6525GA Nijmegen, the Netherlands. Electronic address: h.marks@ncmls.ru.nl.

Abstract

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

PMID:
30472157
DOI:
10.1016/j.stem.2018.10.017

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