H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation

Elife. 2013 Dec 24;2:e01503. doi: 10.7554/eLife.01503.


Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.01503.001.

Keywords: H3K27ac; H3K4me1; KMT2D; MLL4; adipogenesis; cell differentiation; enhancer activation; enhancer chromatin modification; myogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / enzymology*
  • Adipogenesis*
  • Animals
  • Binding Sites
  • Cell Lineage
  • Computational Biology
  • DNA Polymerase II / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation, Developmental
  • Genomics / methods
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism*
  • Humans
  • Mediator Complex / metabolism
  • Methylation
  • Mice
  • Mice, Knockout
  • Muscle Cells / enzymology*
  • Muscle Development*
  • Promoter Regions, Genetic
  • Time Factors
  • Transcription Factors / metabolism
  • Transfection


  • DNA-Binding Proteins
  • Histones
  • Mediator Complex
  • Transcription Factors
  • Histone-Lysine N-Methyltransferase
  • MLL3 protein, mouse
  • MLL4 protein, human
  • MLL4 protein, mouse
  • DNA Polymerase II