SNF5/INI1 inhibits hypertrophic responses through repression of p300/GATA4 in cardiac myocytes

SNF5/INI1 inhibits hypertrophic responses through repression of p300/GATA4 in cardiac myocytes

Akihisa Sugimoto1, Yoichi Sunagawa1,2,3, Yasufumi Katanasaka1, Hiromichi Wada4, Tomohide Takaya3,4, Akira Shimatsu4, Takeshi Kimura3, Masatoshi Fujita2, Koji Hasegawa4, Tatsuya Morimoto1.

  1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
  2. Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  3. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  4. Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.

第14回日本心不全学会学術集会 (東京), 2010/10/08 (口演).

Abstract

Introduction: An intrinsic histone acetyltransferase (HAT), p300 is required for acetylation and the transcriptional activity of GATA4 as well as for cardiomyocyte hypertrophy and the development of heart failure in vivo. By mass spectrometric analyses, we identified SNF5/INI1, a component of the human SWI/SNF chromatin remodeling complex, as a novel GATA4-binding partner. However, the precise functional relationships among p300, GATA4, and SNF5/INI1 remain unknown.

Methods and Results: A series of GST pull-down assays revealed that repeat I domain of SNF5/INI1 bound to the C-terminal zinc finger domain of GATA4 and repeat II domain of SNF5/INI1 bound to the C/H-3 domain of p300. By chromatin immunoprecipitation (ChIP), p300 increased the DNA binding activity of GATA4 onto GATA elements within the endothelin-1 promoter. Furthermore, p300 induced the GATA4-dependent cardiac hypertrophy response gene expression. All of these effects were inhibited by the co-expression of SNF5/INI1. Moreover, overexpression of SNF5/INI1 inhibited phenylephrine-induced hypertrophic response gene promoter activity and cell surface area in cardiomyocytes. Finally, an HDAC inhibitor, trichostatin A, could not rescue SNF5/INI1-induced decrease in p300/GATA4-dependent transcription.

Conclusions: These findings demonstrate that SNF5/INI1 suppressed the p300 HAT activity and formed a functional complex with p300/GATA4 during cardiomyocyte hypertrophy. Further examinations are needed to clarify the precise mechanisms of inhibitory effects of SNF5/INI1 on cardiac hypertrophy.