PRMT4 is a novel coactivator of c-Myb-dependent transcription in haematopoietic cell lines

PLoS Genet. 2013;9(3):e1003343. doi: 10.1371/journal.pgen.1003343. Epub 2013 Mar 7.

Abstract

Protein arginine methyltransferase 4 (PRMT4)-dependent methylation of arginine residues in histones and other chromatin-associated proteins plays an important role in the regulation of gene expression. However, the exact mechanism of how PRMT4 activates transcription remains elusive. Here, we identify the chromatin remodeller Mi2α as a novel interaction partner of PRMT4. PRMT4 binds Mi2α and its close relative Mi2β, but not the other components of the repressive Mi2-containing NuRD complex. In the search for the biological role of this interaction, we find that PRMT4 and Mi2α/β interact with the transcription factor c-Myb and cooperatively coactivate c-Myb target gene expression in haematopoietic cell lines. This coactivation requires the methyltransferase and ATPase activity of PRMT4 and Mi2, respectively. Chromatin immunoprecipitation analysis shows that c-Myb target genes are direct transcriptional targets of PRMT4 and Mi2. Knockdown of PRMT4 or Mi2α/β in haematopoietic cells of the erythroid lineage results in diminished transcriptional induction of c-Myb target genes, attenuated cell growth and survival, and deregulated differentiation resembling the effects caused by c-Myb depletion. These findings reveal an important and so far unknown connection between PRMT4 and the chromatin remodeller Mi2 in c-Myb signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantigens* / genetics
  • Autoantigens* / metabolism
  • Bone Marrow Cells
  • Cell Line
  • Chromatin / genetics*
  • Chromatin Assembly and Disassembly / genetics
  • Gene Expression Regulation
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Methylation
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex* / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex* / metabolism
  • Protein-Arginine N-Methyltransferases* / genetics
  • Protein-Arginine N-Methyltransferases* / metabolism
  • Proto-Oncogene Proteins c-myb* / genetics
  • Proto-Oncogene Proteins c-myb* / metabolism
  • Transcriptional Activation

Substances

  • Autoantigens
  • CHD4 protein, human
  • Chromatin
  • Histones
  • Proto-Oncogene Proteins c-myb
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex

Grant support

This work was funded as part of the FOR531, TRR81, TRR17, and Ba 2292/1 by the DFG (Deutsche Forschungsgemeinschaft), as part of LOEWE (Tumor and Inflammation) by the Land Hessen and by the BMBF (Bundesministerium für Bildung und Forschung) to U-MB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.