Promoter bivalency favors an open chromatin architecture in embryonic stem cells

Nat Genet. 2018 Oct;50(10):1452-1462. doi: 10.1038/s41588-018-0218-5. Epub 2018 Sep 17.


In embryonic stem cells (ESCs), developmental gene promoters are characterized by their bivalent chromatin state, with simultaneous modification by MLL2 and Polycomb complexes. Although essential for embryogenesis, bivalency is functionally not well understood. Here, we show that MLL2 plays a central role in ESC genome organization. We generate a catalog of bona fide bivalent genes in ESCs and demonstrate that loss of MLL2 leads to increased Polycomb occupancy. Consequently, promoters lose accessibility, long-range interactions are redistributed, and ESCs fail to differentiate. We pose that bivalency balances accessibility and long-range connectivity of promoters, allowing developmental gene expression to be properly modulated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Chromatin / chemistry
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly / genetics
  • Drosophila
  • Embryonic Development / genetics
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / physiology*
  • Mice
  • Mouse Embryonic Stem Cells / physiology*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / physiology*
  • Polycomb-Group Proteins / metabolism
  • Promoter Regions, Genetic*
  • Protein Binding / genetics


  • Chromatin
  • Polycomb-Group Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse