Epigenetic sex determinants of cardiometabolic disease and prevention

项目1：心脏代谢性疾病的表观遗传性别差异及预防 摘要 性别影响肥胖和相关的心脏代谢紊乱的发展。性爱也会影响不利的 对他汀类药物的反应，他汀类药物被广泛用于预防心血管疾病。我们已经确定了 性染色体(X和Y)上的基因在男性和女性之间有差异的表达水平 对肥胖和他汀类药物的不良反应都有影响。性染色体基因Kdm5c、Kdm6a、 Kdm5d编码组蛋白去甲基酶，该酶调节组蛋白尾巴上的甲基标记以调节 转录因子获得基因启动子和增强子。我们假设X和Y的基因剂量 染色体组蛋白去甲基酶通过表观遗传学影响心脏代谢健康的性别差异 基因表达的调控。我们将定义这些性别特异性基因剂量的机制 酶影响脂肪组织生物学和他汀类药物引起的线粒体功能障碍。Aim1的目标是 阐明小鼠肥胖和人类脂肪细胞分化中的表观遗传性别差异。我们会 测定Kdm5c、Kdm6a和Kdm5d基因剂量对小鼠性别差异的生理和分子效应 利用小鼠模型、多组学分析和人类诱导的肥胖和脂肪细胞分化 多能干细胞(IPSC)系。具体目标包括：确定 Kdm6a仅影响女性肥胖症，Kdm5d仅影响男性肥胖症； 通过鉴定脂肪细胞中KDM5C、KDM6A和KDM5D的基因组靶点 转录组、染色质景观、组蛋白甲基化和组蛋白去甲基酶基因组结合位点； 识别男性和女性前脂肪细胞分化的性别差异和表观遗传格局 利用几十个人类诱导性多能性细胞系的独特资源。目标2的目标是评估表观遗传学 性别偏见的他汀类药物不良影响的决定因素。我们将利用来自女性和非女性的人类ipscs。 他汀类新发糖尿病患者评估KDM5组蛋白去甲基酶活性在他汀类药物诱导中的作用 线粒体功能障碍，并确定他汀类药物治疗的ipSCs中转录和表观基因组的修饰 来自患有或不患有他汀类药物的新发糖尿病和线粒体功能障碍的女性。这些研究针对的是 未充分研究领域的性别差异对广泛处方药物不良反应的影响。我们将把我们的发现转化为 通过分析人类心脏代谢性状的性别差异探讨其基本机制 广泛的现有人类基因和组学数据，与我们的人类翻译生物信息学合作 核心。

PROJECT 1: Epigenetic Sex Differences in Cardiometabolic Disease and Prevention SUMMARY Sex impacts the development of obesity and related cardiometabolic disorders. Sex also influences adverse responses to statin drugs, which are widely prescribed to prevent cardiovascular disease. We have identified genes on the sex chromosomes (X and Y) that have differential expression levels between males and females and influence both adiposity and adverse effects of statin drugs. The sex chromosome genes Kdm5c, Kdm6a, and Kdm5d encode histone demethylase enzymes, which regulate methyl marks on histone tails to modulate transcription factor access to gene promoters and enhancers. We hypothesize that gene dosage of X and Y chromosome histone demethylases impacts sex differences in cardiometabolic health by epigenetic regulation of gene expression. We will define the mechanisms by which sex-specific gene dosage of these enzymes influence adipose tissue biology and statin induced mitochondrial dysfunction. The goal of Aim1 is to elucidate epigenetic sex differences in mouse adiposity and human adipocyte differentiation. We will determine physiological and molecular effects of Kdm5c, Kdm6a and Kdm5d gene dosage on sex differences in adiposity and adipocyte differentiation using mouse models, multi-omics analyses, and human induced pluripotent stem cell (iPSC) lines. Specific objective include: determining the physiological mechanisms by which Kdm6a influences adiposity exclusively in females, and Kdm5d influences adiposity exclusively in males; identifying the genomic targets of KDM5C, KDM6A, and KDM5D in adipocytes by characterizing the transcriptome, chromatin landscape, histone methylation, and histone demethylase genomic binding sites; and identifying sex differences in human male and female preadipocyte differentiation and epigenetic landscape using a unique resource of several dozen human iPS cell lines. The goal of Aim 2 is to evaluate epigenetic determinants of sex-biased statin adverse effects. We will utilize human iPSCs from women with and without statin new-onset diabetes to assess the role of KDM5 histone demethylase activity in statin-induced mitochondrial dysfunction, and to identify transcriptomic and epigenomic modifications in statin-treated iPSCs from women with or without statin new onset diabetes and mitochondrial dysfunction. These studies address the understudied area of sex differences in adverse effects of widely prescribed drugs. We will translate our findings on fundamental mechanisms underlying sex differences in cardiometabolic traits to humans through analysis of extensive existing human genetic and –omics data, in collaboration with our Human Translational Bioinformatics Core.