Int J Biol Sci 2022; 18(3):1079-1095. doi:10.7150/ijbs.65664 This issue

Research Paper

Multimerization of the GATA4 transcription factor regulates transcriptional activity and cardiomyocyte hypertrophic response

Satoshi Shimizu1,2, Yoichi Sunagawa1,2,3, Naruto Hajika1, Natsumi Yorimitsu1, Yasufumi Katanasaka1,2,3, Masafumi Funamoto1,2, Yusuke Miyazaki1,2,3, Nurmila Sari1, Kana Shimizu1,2, Koji Hasegawa1,2, Tatsuya Morimoto1,2,3✉

1. Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
2. Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
3. Shizuoka General Hospital, Shizuoka, Japan

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Citation:
Shimizu S, Sunagawa Y, Hajika N, Yorimitsu N, Katanasaka Y, Funamoto M, Miyazaki Y, Sari N, Shimizu K, Hasegawa K, Morimoto T. Multimerization of the GATA4 transcription factor regulates transcriptional activity and cardiomyocyte hypertrophic response. Int J Biol Sci 2022; 18(3):1079-1095. doi:10.7150/ijbs.65664. Available from https://www.ijbs.com/v18p1079.htm

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Abstract

Graphic abstract

The activation of the GATA-binding factor 4 (GATA4) transcription factor induces cardiac hypertrophy and heart failure. The multimerization of transcription factors often plays an important role in the regulation of transcriptional activity. Here, we report that the GATA4 transcription factor forms a homomultimer and that residues 308-326 of GATA4 are necessary for its multimerization. The acetylation of GATA4 by the transcriptional co-activator p300 induces the multimerization of GATA4 and activates its DNA binding activity. In addition, we found that the suppression of GATA4 multimerization did not reduce its acetylation, but repressed GATA4/p300-induced gene transcription. Furthermore, the inhibition of GATA4 multimerization suppressed phenylephrine (PE)-induced hypertrophic response in cardiomyocytes. This study demonstrates that the multimerization of GATA4 during the p300-induced acetylation of GATA4 activates the transcription of hypertrophic response genes, which leads to cardiomyocyte hypertrophy. Therefore, the inhibition of GATA4 homomultimerization could serve as a potential therapeutic strategy for the development of novel drugs against heart failure.

Keywords: GATA4, Multimerization, Acetylation, Cardiomyocyte, Hypertrophy