Acetylation of myocardin is required for the activation of cardiac and smooth muscle genes

J Biol Chem. 2012 Nov 9;287(46):38495-504. doi: 10.1074/jbc.M112.353649. Epub 2012 Sep 23.

Abstract

Myocardin belongs to the SAF-A/B, Acinus, PIAS (SAP) domain family of transcription factors and is specifically expressed in cardiac and smooth muscle. Myocardin functions as a transcriptional coactivator of SRF and is sufficient and necessary for smooth muscle gene expression. We have previously found that myocardin induces the acetylation of nucleosomal histones surrounding SRF-binding sites in the control regions of cardiac and smooth muscle genes through recruiting chromatin-modifying enzyme p300, yet no studies have determined whether myocardin itself is similarly modified. In this study, we show that myocardin is a direct target for p300-mediated acetylation. p300 acetylates lysine residues at the N terminus of the myocardin protein. Interestingly, a direct interaction between p300 and myocardin, which is mediated by the C terminus of myocardin, is required for the acetylation event. Acetylation of myocardin by p300 enhances the association of myocardin and SRF as well as the formation of the myocardin-SRF-CArG box ternary complex. Conversely, acetylation of myocardin decreases the binding of histone deacetylase 5 (HDAC5) to myocardin. Acetylation of myocardin is required for myocardin to activate smooth muscle genes. Our study demonstrates that acetylation plays a key role in modulating myocardin function in controlling cardiac and smooth muscle gene expression.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • COS Cells
  • Chromatin / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Histones / genetics
  • Mice
  • Models, Biological
  • Muscle, Smooth / metabolism*
  • Myocardium / metabolism*
  • Nuclear Proteins / metabolism*
  • Serum Response Factor / metabolism
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Transcriptional Activation
  • p300-CBP Transcription Factors / metabolism

Substances

  • Chromatin
  • Histones
  • Nuclear Proteins
  • Serum Response Factor
  • Trans-Activators
  • myocardin
  • p300-CBP Transcription Factors