Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
Int J Biol Sci. 2022 Jan 1;18(3):1079-1095. doi: 10.7150/ijbs.65664. eCollection 2022.
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.
GATA 结合因子 4（GATA4）转录因子的激活可诱导心肌肥厚和心力衰竭。转录因子的多聚化在转录活性的调节中经常起着重要作用。在这里，我们报告 GATA4 转录因子形成同源多聚体，并且 GATA4 的残基 308-326 对于其多聚化是必需的。转录共激活因子 p300 对 GATA4 的乙酰化诱导 GATA4 的多聚化并激活其 DNA 结合活性。此外，我们发现抑制 GATA4 多聚化不会减少其乙酰化，但会抑制 GATA4/p300 诱导的基因转录。此外，抑制 GATA4 多聚化可抑制心肌细胞中苯肾上腺素（PE）诱导的肥厚反应。这项研究表明，在 p300 诱导的 GATA4 乙酰化过程中 GATA4 的多聚化激活了肥厚反应基因的转录，从而导致心肌细胞肥大。因此，抑制 GATA4 同源多聚体的形成可能成为开发针对心力衰竭的新型药物的潜在治疗策略。
