组蛋白去甲基化酶JMJD3调控病理性心肌肥大的表观修饰机制研究

组蛋白修饰和DNA甲基化是两种重要的表观修饰方式，是表观遗传学的核心内容，具有潜在可逆性及可干预性。病理性心肌肥大具有明显的表观遗传特征。我们既往对Ⅲ类组蛋白去乙酰化SIRTs家族与心肌肥大的关系进行了系统研究，近期研究又发现组蛋白去甲基化酶JMJD3也以酶活性依赖性方式诱导心肌肥大，并且与心功能密切相关的β-MHC基因启动子区域的结合明显增加。本课题将从组蛋白甲基化修饰对DNA甲基化调节角度，研究：1）JMJD3对β-MHC的转录及表达的影响是否涉及组蛋白甲基化及DNA甲基化2个方面？2）利用DNA甲基化芯片筛查过表达JMJD3模型动物与心肌肥大密切相关的基因，研究JMJD3是否通过降低组蛋白H3K27位点甲基化而调节DNA甲基化及其调节机制。通过本课题的实施，我们将明确JMJD3介导的组蛋白去甲基化对相关基因DNA甲基化调节及机制，从表观修饰角度探索病理性心肌肥大干预策略及潜在靶点。

Histone modification and DNA methylation, two major types of epigenetic modifications which are reversible, remain potentially important pathogenic mechanisms in diseases and conceivably represent therapeutic targets. Pathological myocardial hypertrophy demonstrates obvious epigenetic features. Our previous studies have systemically identified the role of class III HDAC sirtuins (SIRTs) represent in pathological myocardial hypertrophy. Recently, our preliminary studies indicate that histone demethylase JMJD3 also plays a pivotal regulatory role in the development of myocardial hypertrophy, dependent on its enzyme activity. In particular, JMJD3 combinds to the gene promoter regions of β-MHC, which is regarded as an important biomarker for cardiac function. In this proposed study, the regulation of JMJD3 in pathological myocardial hypertrophy will be investigated by focusing on its interplay with histone modification and DNA methylation, including: 1) to test the involvement of histone modification and DNA methylation in the regulation of JMJD3 in β-MHC transcription and expression; 2) to investigate whether or not JMJD3 alters DNA methylation and β-MHC transcription through regulating H3K27 methylation. By investigating the effects and mechanisms of JMJD3-induced histone demethylation on target genes DNA methylation, the study will pave the way to the therapeutic strategies and potential targets of pathological myocardial hypertrophy via epigenetic modifications.