Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification

Mol Cell. 2017 Feb 2;65(3):460-475.e6. doi: 10.1016/j.molcel.2017.01.013.


The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and epigenetic states at cis-regulatory elements. Here, we show that in addition to implementing H3K4me3 at promoters of bivalent genes, Mll2 (KMT2B)/COMPASS can also implement H3K4me3 at a subset of non-TSS regulatory elements, a subset of which shares epigenetic signatures of active enhancers. Our mechanistic studies reveal that association of Mll2's CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3. Although Mll2/COMPASS is required for H3K4me3 implementation on thousands of loci, generation of catalytically mutant MLL2/COMPASS demonstrated that H3K4me3 implemented by this enzyme was essential for expression of a subset of genes, including those functioning in the control of transcriptional programs during embryonic development. Our findings suggest that not all H3K4 trimethylations implemented by MLL2/COMPASS are functionally equivalent.

Keywords: CXXC domain; Histone-Lysine N-Methyltransferase; Kmt2b; Mll2; chromatin; embryonic development; gene expression regulation; histone; mouse embryonic stem cell; primordial germ cell.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Genetic Speciation
  • Germ Cells / cytology*
  • Germ Cells / metabolism
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism*
  • Humans
  • Mice
  • Mouse Embryonic Stem Cells / cytology*
  • Mouse Embryonic Stem Cells / metabolism
  • Myeloid-Lymphoid Leukemia Protein / chemistry
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Promoter Regions, Genetic
  • Protein Domains


  • DNA-Binding Proteins
  • Histones
  • KMT2D protein, human
  • Neoplasm Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse