Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy

Gwang Hyeon Eom, Yoon Seok Nam, Jae Gyun Oh, Nakwon Choe, Hyun Ki Min, Eun Kyung Yoo, Gaeun Kang, Vu Hong Nguyen, Jung Joon Min, Jong Keun Kim, In Kyu Lee, Rhonda Bassel-Duby, Eric N. Olson, Woo Jin Park, Hyun Kook

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

RATIONALE:: Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear. OBJECTIVE:: Recently, we suggested that casein kinase 2α1-dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5. METHODS AND RESULTS:: Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress-induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced. CONCLUSIONS:: Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)1133-1143
Number of pages11
JournalCirculation research
Volume114
Issue number7
DOIs
StatePublished - Mar 28 2014

Keywords

  • acetylation
  • cardiomyopathy, hypertrophic
  • histone deacetylase 2
  • histone deacetylase 5, mouse
  • p300-CBP-associated factor
  • protein processing, post-translational

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Eom, G. H., Nam, Y. S., Oh, J. G., Choe, N., Min, H. K., Yoo, E. K., Kang, G., Nguyen, V. H., Min, J. J., Kim, J. K., Lee, I. K., Bassel-Duby, R., Olson, E. N., Park, W. J., & Kook, H. (2014). Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy. Circulation research, 114(7), 1133-1143. https://doi.org/10.1161/CIRCRESAHA.114.303429