Epigenetic drift of the Aging Heart in Drosophila

果蝇衰老心脏的表观遗传漂移

• 批准号: 10528337
• 负责人: Maria Clara Guida
• 金额: $ 29.25万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528337
• 关键词: Adult; Affect; Age; Aging; Animal Model; Biological; CRISPR/Cas technology; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Complex; DNA; Data; Drosophila genus; EZH2 gene; Economics; Epigenetic Process; Evaluation; Fruit; Future; Gene Expression; Gene Expression Profiling; Gene Silencing; Genes; Genetic; Genome; Genomic Instability; Genomics; Goals; Heart; Heart Abnormalities; Heart Diseases; Heart failure; Histones; Homeostasis; Human; Human Pathology; Incidence; Life; Link; Longevity; Maintenance; Measurement; Methods; Methyltransferase; Modeling; Modification; Mutation; Myocardial dysfunction; Observational Study; Older Population; Pathology; Pathway interactions; Polycomb; Population; Prevention; Process; Publishing; Reporting; Reproducibility; Risk Factors; Rodent; Running; Techniques; Testing; Therapeutic; United States; Validation; XCL1 gene; age effect; age related; base; candidate validation; cardiac pacing; cardioprotection; cell type; comparative; detection of nutrient; epigenetic profiling; epigenome; experimental study; fly; heart function; improved; in vivo; inhibitor; innovation; knock-down; mitochondrial dysfunction; mutant; new technology; new therapeutic target; novel; preservation; prevent; programs; proteostasis; restoration; screening; social; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Aging is a complex process accompanied by loss of proteostasis, genomic instability, deregulated nutrient sensing, mitochondrial dysfunction, and epigenetic alterations. Accordingly, age is the main risk factor for major human pathologies, including heart disease, the leading cause of death worldwide. Cardiomyocytes are long- lived cells, thus particularly vulnerable to the detrimental effects of aging. Evidence already suggests that the maintenance of the epigenome becomes more error-prone with age, leading to so-called “epigenetic drift”, or accumulation of epigenetic alterations. Interestingly, manipulation of certain epigenetic and chromatin modifiers was found to expand lifespan in different animal models. For instance, heterozygous mutant flies for components of the Polycomb repressive complex 2 (PRC2) were reported to have reduced overall H3K27me3 repressive marks with age, and an increased lifespan. However, little is known about the epigenetic mechanisms that may preserve healthy cardiac aging. Our preliminary data showed that reduced function of PRC2 components can prevent cardiac aging. Importantly, age-related cardioprotection was also found when flies were treated with an inhibitor of the H3K27me3 methyltransferase, EZH2, similarly to the rescue of lipotoxic cardiomyopathy we recently published. Therefore, we hypothesize that epigenetic modifications -particularly H3K27me3 cardiac signatures- undergo age-related changes, leading to abnormal cardiac gene expression and progressive heart dysfunction. Here we propose to use the Drosophila aging heart model, which has several advantages including short lifespan, less genetic redundancy, and conserved biological pathways, to elucidate the (epi)genetic control of age-related decline in heart function and to identify novel therapeutic targets for the treatment and prevention of age-associated heart disease. Importantly, we have optimized gene expression and epigenetic profiling techniques to be run in the fly heart. We will 1) Characterize gene expression and DNA accessibility in exact same cells in young and old hearts by running state of the art single nuclei Multiome ATAC + gene expression 2) Investigate the age-related changes in active and repressive histone marks in the Drosophila heart and their functional consequences using the novel CUT&RUN technique, and 3) Identify epigenetic regulators that participate in cardiac aging by a targeted in vivo screen in Drosophila. Since epigenetic changes are reversible, we anticipate that manipulation of epigenetic regulators can improve cardiac function by preventing the deleterious effects of aging on cardiomyocyte’s epigenetic homeostasis through the restoration of young-like gene programs.

项目概要 衰老是一个复杂的过程，伴随着蛋白质稳态的丧失、基因组不稳定、营养失调 传感、线粒体功能障碍和表观遗传改变。因此，年龄是重大疾病的主要危险因素 人类疾病，包括心脏病，它是全世界死亡的主要原因。心肌细胞长 活细胞，因此特别容易受到衰老的不利影响。已有证据表明 随着年龄的增长，表观基因组的维护变得更容易出错，导致所谓的“表观遗传漂移”，或者 表观遗传改变的积累。有趣的是，某些表观遗传和染色质修饰剂的操纵 被发现可以延长不同动物模型的寿命。例如，杂合突变体果蝇的成分 据报道，Polycomb 抑制复合体 2 (PRC2) 的整体 H3K27me3 抑制降低 随着年龄的增长和寿命的延长而留下痕迹。然而，人们对表观遗传机制知之甚少。 保持健康的心脏老化。我们的初步数据表明，PRC2 组件功能的减少可以 防止心脏老化。重要的是，当果蝇接受某种药物治疗时，还发现了与年龄相关的心脏保护作用。 H3K27me3 甲基转移酶 EZH2 抑制剂，与脂毒性心肌病的拯救类似，我们 最近发布。因此，我们假设表观遗传修饰 - 特别是 H3K27me3 心脏 特征——经历与年龄相关的变化，导致心脏基因表达异常和进行性进展 心脏功能障碍。这里我们建议使用果蝇衰老心脏模型，它有几个优点 包括寿命短、遗传冗余少和生物途径保守，以阐明 对与年龄相关的心功能下降进行（表观）遗传控制，并确定新的治疗靶点 治疗和预防与年龄相关的心脏病。重要的是，我们优化了基因表达 在果蝇心脏中运行的表观遗传分析技术。我们将 1) 表征基因表达和 DNA 通过运行最先进的单核多组学，可访问年轻和年老心脏中完全相同的细胞 ATAC + 基因表达 2) 研究活性组蛋白标记和抑制性组蛋白标记与年龄相关的变化 使用新颖的 CUT&RUN 技术观察果蝇心脏及其功能后果，以及 3) 通过果蝇体内靶向筛选来鉴定参与心脏衰老的表观遗传调节因子。 由于表观遗传变化是可逆的，我们预计表观遗传调节因子的操纵可以改善 通过防止衰老对心肌细胞表观遗传稳态的有害影响来改善心脏功能 通过恢复年轻基因程序。