Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4

Genes Dev. 2012 Dec 15;26(24):2749-62. doi: 10.1101/gad.203356.112.


Mixed-lineage leukemia 4 (MLL4; also called MLL2 and ALR) enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3), a hallmark of gene activation. However, how MLL4-deposited H3K4me3 interplays with other histone marks in epigenetic processes remains largely unknown. Here, we show that MLL4 plays an essential role in differentiating NT2/D1 stem cells by activating differentiation-specific genes. A tandem plant homeodomain (PHD(4-6)) of MLL4 recognizes unmethylated or asymmetrically dimethylated histone H4 Arg 3 (H4R3me0 or H4R3me2a) and is required for MLL4's nucleosomal methyltransferase activity and MLL4-mediated differentiation. Kabuki syndrome mutations in PHD(4-6) reduce PHD(4-6)'s binding ability and MLL4's catalytic activity. PHD(4-6)'s binding strength is inhibited by H4R3 symmetric dimethylation (H4R3me2s), a gene-repressive mark. The protein arginine methyltransferase 7 (PRMT7), but not PRMT5, represses MLL4 target genes by up-regulating H4R3me2s levels and antagonizes MLL4-mediated differentiation. Consistently, PRMT7 knockdown increases MLL4-catalyzed H3K4me3 levels. During differentiation, decreased H4R3me2s levels are associated with increased H3K4me3 levels at a cohort of genes, including many HOXA and HOXB genes. These findings indicate that the trans-tail inhibition of MLL4-generated H3K4me3 by PRMT7-regulated H4R3me2s may result from H4R3me2s's interference with PHD(4-6)'s binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation.

Publication types

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

MeSH terms

  • Cell Differentiation
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Histones / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Intermediate Filament Proteins / metabolism
  • Methylation
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neurons / cytology
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Arginine N-Methyltransferases / genetics
  • Stem Cells / cytology


  • DNA-Binding Proteins
  • Histones
  • Homeodomain Proteins
  • Intermediate Filament Proteins
  • NES protein, human
  • Nerve Tissue Proteins
  • Nestin
  • HoxA protein
  • PRMT7 protein, human
  • Protein-Arginine N-Methyltransferases
  • MLL4 protein, human