组蛋白去甲基化酶UTX介导的表观遗传调控在针刺抗心肌缺血损伤中的作用及机制研究

The mechanism research of acupuncture against myocardial ischemia has gone deep into the level of genetics, but the mechanism remains unclear. Histone modifications can modulate the expression of target genes effectively against myocardial ischemia. Recent studies have showed histone demethylase UTX played an important role in the processes of cardiac development, function-maintaining of cardiomyocyte and the tissue repair. We have previously proved that acupuncture altered genome-wide gene expressions through epigenetic modulations, and also found the expression alterations of UTX and H3K27me3 during the process of myocardial ischemia. So we now propose that acupuncture could play anti-ischemic roles through regulation of histone demethylation at functional gene loci. To check this hypothesis, we will first generate cardiac specific knockout mice in whose hearts the demethylase UTX controlling demethylation of H3K27me3 is knocked out. Using these mice, we will check the protective effects of acupuncture on ischemia, and then determine the profiles of gene expression and H3K27me3 binding patterns at gene loci by using RNA-seq and ChIP-assay techniques, respectively. Our research will provide solid evidences that mechanism of acupuncture against myocardial ischemic injury is mediated by the regulation of histone methylation, which could shed light on mechanistic studies and clinical applications for acupuncture.

针刺保护心肌缺血机制研究已深入基因水平，但仍未能完全阐明。组蛋白修饰介导的表观遗传调控能有效调控基因表达，实现心肌保护。最新研究证实H3K27去甲基化酶UTX在心脏发育、维持心肌细胞功能及组织损伤修复中扮演重要角色，是心肌保护研究的热点。我们率先证实针刺作用与表观遗传调控密切相关；预实验结果显示，针刺能有效改变缺血心肌基因表达谱，并发现在该过程中UTX表达下降，H3K27me3水平升高，故提出“UTX介导的表观遗传调控是针刺实现心肌缺血损伤保护的关键机制”。围绕该假说，根据中医针灸理论，以心脏特异性Utx基因敲除小鼠行心肌缺血造模，在充分评价针刺效应基础上，用高通量测序技术RNA-seq获得针刺前后差异基因；ChIP-assay对H3K27me3在基因上的结合特征进行系统生物学分析，揭示组蛋白甲基化介导针刺保护缺血心肌的作用，丰富针灸学科学内涵，为其临床运用提供科学的实验依据。

针刺保护心肌缺血机制研究已深入基因水平，但仍未能完全阐明。组蛋白修饰介导的表观遗传调控能有效调控基因表达，实现心肌保护。最新研究证实H3K27去甲基化酶UTX在心脏发育、维持心肌细胞功能及组织损伤修复中扮演重要角色，是心肌保护研究的热点。我们率先证实针刺作用与表观遗传调控密切相关；根据中医针灸理论，以心脏特异性Utx基因敲除小鼠行心肌缺血造模，充分明确了针刺的保护效应，用高通量测序技术RNA-seq获得了缺血心肌基因表达谱。我们发现在该过程中UTX表达下降，但H3K27me3水平变化未见明显统计学差异，因此UTX介导组蛋白H3K27me3去甲基化可能并非MI过程发挥重要作用，追踪最新研究，我们通过实验证实UTX可通过催化转录因子β-catenin的去甲基化调控Hif1α-A2b轴可能是实现针刺的心肌缺血保护效应的机制之一。