Crosstalk Between C/EBPbeta Phosphorylation, Arginine Methylation, and SWI/SNF/Mediator Implies an Indexing Transcription Factor Code

EMBO J. 2010 Mar 17;29(6):1105-15. doi: 10.1038/emboj.2010.3. Epub 2010 Jan 28.

Abstract

Cellular signalling cascades regulate the activity of transcription factors that convert extracellular information into gene regulation. C/EBPbeta is a ras/MAPkinase signal-sensitive transcription factor that regulates genes involved in metabolism, proliferation, differentiation, immunity, senescence, and tumourigenesis. The protein arginine methyltransferase 4 PRMT4/CARM1 interacts with C/EBPbeta and dimethylates a conserved arginine residue (R3) in the C/EBPbeta N-terminal transactivation domain, as identified by mass spectrometry of cell-derived C/EBPbeta. Phosphorylation of the C/EBPbeta regulatory domain by ras/MAPkinase signalling abrogates the interaction between C/EBPbeta and PRMT4/CARM1. Differential proteomic screening, protein interaction studies, and mutational analysis revealed that methylation of R3 constraines interaction with SWI/SNF and Mediator complexes. Mutation of the R3 methylation site alters endogenous myeloid gene expression and adipogenic differentiation. Thus, phosphorylation of the transcription factor C/EBPbeta couples ras signalling to arginine methylation and regulates the interaction of C/EBPbeta with epigenetic gene regulatory protein complexes during cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arginine / metabolism*
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Methylation
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Chromosomal Proteins, Non-Histone
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • Arginine
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1