ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes

Mol Cell. 2013 Mar 28;49(6):1108-20. doi: 10.1016/j.molcel.2013.01.033. Epub 2013 Feb 28.

Abstract

Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Substitution
  • Animals
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • Enzyme Stability
  • Gene Expression
  • HeLa Cells
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / chemistry*
  • Histones / chemistry*
  • Histones / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Methylation
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Myeloid-Lymphoid Leukemia Protein / chemistry*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nucleosomes
  • Protein Interaction Domains and Motifs
  • Signal Transduction
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Ubiquitin C / chemistry
  • Ubiquitin-Conjugating Enzymes / chemistry
  • Ubiquitination*
  • Xenopus
  • Xenopus Proteins / chemistry

Substances

  • ASH2L protein, human
  • DNA-Binding Proteins
  • Histones
  • Homeodomain Proteins
  • KMT2A protein, human
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Nucleosomes
  • Transcription Factors
  • Ubiquitin C
  • Xenopus Proteins
  • homeobox protein HOXA9
  • Myeloid-Lymphoid Leukemia Protein
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • UBE2D3 protein, human
  • Ubiquitin-Conjugating Enzymes