WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development

Cell. 2005 Jun 17;121(6):859-72. doi: 10.1016/j.cell.2005.03.036.

Abstract

Histone H3 lysine 4 (K4) methylation has been linked to the transcriptional activation in a variety of eukaryotic species. Here we show that a common component of MLL1, MLL2, and hSet1 H3 K4 methyltransferase complexes, the WD40-repeat protein WDR5, directly associates with histone H3 di- and trimethylated at K4 and with H3-K4-dimethylated nucleosomes. WDR5 is required for binding of the methyltransferase complex to the K4-dimethylated H3 tail as well as for global H3 K4 trimethylation and HOX gene activation in human cells. WDR5 is essential for vertebrate development, in that WDR5-depleted X. laevis tadpoles exhibit a variety of developmental defects and abnormal spatial Hox gene expression. Our results are the first demonstration that a WD40-repeat protein acts as a module for recognition of a specific histone modification and suggest a mechanism for reading and writing an epigenetic mark for gene activation.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Genes, Homeobox / genetics
  • Genes, Homeobox / physiology
  • Heterotrimeric GTP-Binding Proteins / genetics
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism*
  • Humans
  • Lysine / metabolism*
  • Macromolecular Substances / metabolism
  • Methylation
  • Microfilament Proteins / metabolism*
  • Nucleosomes / metabolism
  • Vertebrates / embryology*
  • Xenopus laevis / embryology
  • Xenopus laevis / genetics
  • Xenopus laevis / physiology

Substances

  • Histones
  • Macromolecular Substances
  • Microfilament Proteins
  • Nucleosomes
  • WDR5 protein, human
  • Histone-Lysine N-Methyltransferase
  • Heterotrimeric GTP-Binding Proteins
  • Lysine