Epigenomic analysis of gastrulation identifies a unique chromatin state for primed pluripotency

Nat Genet. 2020 Jan;52(1):95-105. doi: 10.1038/s41588-019-0545-1. Epub 2019 Dec 16.

Abstract

Around implantation, the epiblast (Epi) transits from naïve to primed pluripotency, before giving rise to the three germ layers. How chromatin is reconfigured during this developmental window remains poorly understood. We performed a genome-wide investigation of chromatin landscapes during this period. We find that enhancers in ectoderm are already pre-accessible in embryonic day 6.5 (E6.5) Epi when cells enter a primed pluripotent state. Unexpectedly, strong trimethylation of histone H3 at lysine 4 (H3K4me3) emerges at developmental gene promoters in E6.5 Epi and positively correlates with H3K27me3, thus establishing bivalency. These genes also show enhanced spatial interactions. Both the strong bivalency and spatial clustering are virtually absent in preimplantation embryos and are markedly reduced in fate-committed lineages. Finally, we show that KMT2B is essential for establishing bivalent H3K4me3 at E6.5 but becomes partially dispensable later. Its deficiency leads to impaired activation of developmental genes and subsequent embryonic lethality. Thus, our data characterize lineage-specific chromatin reconfiguration and a unique chromatin state for primed pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / genetics*
  • DNA Methylation
  • Embryo, Mammalian / cytology*
  • Embryo, Mammalian / metabolism
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Epigenesis, Genetic
  • Epigenomics / methods*
  • Female
  • Gastrulation*
  • Gene Expression Regulation, Developmental*
  • Histone-Lysine N-Methyltransferase / physiology*
  • Histones / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid-Lymphoid Leukemia Protein / physiology*

Substances

  • Chromatin
  • Histones
  • histone H3 trimethyl Lys4
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse