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J. Biol. Chem., Vol. 280, Issue 20, 19682-19688, May 20, 2005

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Acetylation of GATA-4 Is Involved in the Differentiation of Embryonic Stem Cells into Cardiac Myocytes^*

Teruhisa Kawamura, Koh Ono, Tatsuya Morimoto, Hiromichi Wada, Maretoshi Hirai, Kyoko Hidaka¶, Takayuki Morisaki¶, Toshio Heike||, Tatsutoshi Nakahata||, Toru Kita, and Koji Hasegawa**

From the Division of Translational Research, Kyoto Medical Center, National Hospital Organization, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, the Departments of Cardiovascular Medicine and ^||Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, and the ^¶Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan

Differentiation of embryonic stem (ES) cells into cardiac myocytes requires activation of a cardiac-specific gene program. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) govern gene expression patterns by being recruited to target genes through association with specific transcription factors. One of the HATs, p300, serves as a coactivator of cardiac-specific transcription factors such as GATA-4. The HAT activity of p300 is required for acetylation and DNA binding of GATA-4 and its full transcriptional activity as well as for promotion of a transcriptionally active chromatin configuration. However, the roles of HATs and HDACs in post-translational modification of GATA-4 during the differentiation of ES cells into cardiac myocytes remain unknown. In an ES cell model of developing embryoid bodies, an acetylated form of GATA-4 and its DNA binding increased concomitantly with the expression of p300 during the differentiation of ES cells into cardiac myocytes. Treatment of ES cells with trichostatin A (TSA), a specific HDAC inhibitor, induced acetylation of histone-3/4 near GATA sites within the atrial natriuretic factor promoter. In addition, TSA augmented the increase in an acetylated form of GATA-4 and its DNA binding during the ES cell differentiation. Finally, TSA facilitated the expression of green fluorescence protein under the control of the cardiac-specific Nkx-2.5 promoter and of endogenous cardiac -myosin heavy chain during the differentiation. These findings demonstrate that acetylation of GATA-4 as well as of histones is involved in the differentiation of ES cells into cardiac myocytes.

Received for publication, November 3, 2004 , and in revised form, February 9, 2005.

^* This work was supported in part by the Advanced and Innovational Research Program in Life Science and grants from the Ministry of Education, Science, and Culture of Japan (to T. Kita and K. Hasegawa). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

^** To whom correspondence should be addressed. Tel.: 81-75-641-9161; Fax: 81-75-641-9252; E-mail: koj{at}kuhp.kyoto-u.ac.jp.

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