Genome-Wide Studies Reveal that H3K4me3 Modification in Bivalent Genes Is Dynamically Regulated during the Pluripotent Cell Cycle and Stabilized upon Differentiation

Mol Cell Biol. 2015 Dec 7;36(4):615-27. doi: 10.1128/MCB.00877-15. Print 2016 Feb 15.


Stem cell phenotypes are reflected by posttranslational histone modifications, and this chromatin-related memory must be mitotically inherited to maintain cell identity through proliferative expansion. In human embryonic stem cells (hESCs), bivalent genes with both activating (H3K4me3) and repressive (H3K27me3) histone modifications are essential to sustain pluripotency. Yet, the molecular mechanisms by which this epigenetic landscape is transferred to progeny cells remain to be established. By mapping genomic enrichment of H3K4me3/H3K27me3 in pure populations of hESCs in G2, mitotic, and G1 phases of the cell cycle, we found striking variations in the levels of H3K4me3 through the G2-M-G1 transition. Analysis of a representative set of bivalent genes revealed that chromatin modifiers involved in H3K4 methylation/demethylation are recruited to bivalent gene promoters in a cell cycle-dependent fashion. Interestingly, bivalent genes enriched with H3K4me3 exclusively during mitosis undergo the strongest upregulation after induction of differentiation. Furthermore, the histone modification signature of genes that remain bivalent in differentiated cells resolves into a cell cycle-independent pattern after lineage commitment. These results establish a new dimension of chromatin regulation important in the maintenance of pluripotency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Cell Differentiation
  • Cell Line
  • Chromatin / genetics*
  • Chromatin / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Developmental*
  • Genome-Wide Association Study
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / genetics*
  • Histones / metabolism
  • Human Embryonic Stem Cells / cytology*
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Neoplasm Proteins / metabolism


  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • KMT2A protein, human
  • KMT2D protein, human
  • Neoplasm Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase