Carm1 regulates Pax7 transcriptional activity through MLL1/2 recruitment during asymmetric satellite stem cell divisions

Cell Stem Cell. 2012 Sep 7;11(3):333-45. doi: 10.1016/j.stem.2012.07.001. Epub 2012 Aug 2.

Abstract

In skeletal muscle, asymmetrically dividing satellite stem cells give rise to committed satellite cells that transcribe the myogenic determination factor Myf5, a Pax7-target gene. We identified the arginine methyltransferase Carm1 as a Pax7 interacting protein and found that Carm1 specifically methylates multiple arginines in the N terminus of Pax7. Methylated Pax7 directly binds the C-terminal cleavage forms of the trithorax proteins MLL1/2 resulting in the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3K4 methyltransferase complex to regulatory enhancers and the proximal promoter of Myf5. Finally, Carm1 is required for the induction of de novo Myf5 transcription following asymmetric satellite stem cell divisions. We defined the C-terminal MLL region as a reader domain for the recognition of arginine methylated proteins such as Pax7. Thus, arginine methylation of Pax7 by Carm1 functions as a molecular switch controlling the epigenetic induction of Myf5 during satellite stem cell asymmetric division and entry into the myogenic program.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Arginine / metabolism
  • Cell Division / genetics*
  • DNA / metabolism
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation
  • Mice
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Myogenic Regulatory Factor 5 / metabolism
  • PAX7 Transcription Factor / chemistry
  • PAX7 Transcription Factor / genetics*
  • PAX7 Transcription Factor / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Satellite Cells, Skeletal Muscle / cytology*
  • Satellite Cells, Skeletal Muscle / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Substrate Specificity
  • Transcription, Genetic*

Substances

  • Histones
  • Myogenic Regulatory Factor 5
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Myeloid-Lymphoid Leukemia Protein
  • DNA
  • Arginine
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse
  • Lysine