Zhou Wei, Jiang Dagui, Tian Jie, Liu Lingjuan, Lu Tiewei, Huang Xupei, Sun Huichao
Heart Centre, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.
China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.
Genes Dis. 2018 Oct 15;6(3):318-325. doi: 10.1016/j.gendis.2018.10.002. eCollection 2019 Sep.
GATA4 is a particularly important cardiogenic transcription factor and serves as a potent driver of cardiogenesis. Recent progress in the field has made it clear that histone acetylation can influence gene expression through changing the structure of chromatin. Our previous research had revealed that hypo-acetylation could repress expression in cardiocytes, however the underlying mechanism by which this occurred was still unclear. To reveal the mechanism of histone acetylation involved in the regulation of transcription, we concentrated on P300, one of the important histone acetyltransferase associated with cardiogenesis. We found that P300 participated in expression through regulating histone acetylation in embryonic mouse hearts. RNAi-mediated downregulation of P300 modulated the global acetylation of H3 and the acetylation of H3K4, H3K9, and H3K27 in and Tbx5 promoters. Interestingly, there was an obvious inhibition of transcription, whereas Tbx5 was not influenced. Furthermore, SGC-CBP30, the selective inhibitor of the bromodomain in CBP/P300, downregulated transcription by repressing the acetylation of H3K4, H3K9, and H3K27 in the promoters. Taken together, our results identified that acetylation of H3K4, H3K9, and H3K27 mediated by P300 plays an important role in regulation of expression in cardiogenesis.
GATA4是一种特别重要的心脏发生转录因子，是心脏发生的有力驱动因素。该领域的最新进展已明确表明，组蛋白乙酰化可通过改变染色质结构来影响基因表达。我们之前的研究表明，低乙酰化可抑制心肌细胞中的表达，然而其发生的潜在机制仍不清楚。为了揭示参与转录调控的组蛋白乙酰化机制，我们聚焦于P300，它是与心脏发生相关的重要组蛋白乙酰转移酶之一。我们发现P300通过调节胚胎小鼠心脏中的组蛋白乙酰化参与表达。RNAi介导的P300下调调节了H3的整体乙酰化以及和Tbx5启动子中H3K4、H3K9和H3K27的乙酰化。有趣的是，转录受到明显抑制，而Tbx5不受影响。此外，CBP/P300中溴结构域的选择性抑制剂SGC-CBP30通过抑制启动子中H3K4、H3K9和H3K27的乙酰化来下调转录。综上所述，我们的结果表明，由P300介导的H3K4、H3K9和H3K27的乙酰化在心脏发生过程中表达的调控中起重要作用。
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