Epigenetic drift of the Aging Heart in Drosophila

果蝇衰老心脏的表观遗传漂移

• 批准号: 10672241
• 负责人: Maria Clara Guida
• 金额: $ 24.38万
• 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 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672241
• 关键词: Adult; Affect; Age; Aging; Animal Model; Biological; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; Data; Drosophila genus; EZH2 gene; Economics; Epigenetic Process; Evaluation; Future; Gene Expression; Gene Expression Profiling; Gene Silencing; Genes; Genetic; Genome; Genomic Instability; Genomics; Goals; Heart; Heart Abnormalities; Heart Diseases; Heart failure; Heterozygote; 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; candidate identification; 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; multiple omics; 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.

项目摘要 衰老是一个复杂的过程，伴随着蛋白质稳态的丧失，基因组的不稳定性， 传感、线粒体功能障碍和表观遗传改变。因此，年龄是主要的风险因素。 人类疾病，包括心脏病，这是全世界死亡的主要原因。心肌细胞很长- 活细胞，因此特别容易受到衰老的不利影响。有证据表明， 随着年龄的增长，表观基因组的维持变得更容易出错，导致所谓的“表观遗传漂变”，或 表观遗传改变的积累。有趣的是，操纵某些表观遗传和染色质修饰剂， 在不同的动物模型中发现可以延长寿命。例如，杂合突变果蝇的成分 的Polycomb阻遏复合物2（PRC 2）被报道具有降低的总体H3 K27 me 3阻遏作用。 随着年龄的增长和寿命的增加而标记。然而，很少有人知道表观遗传机制， 保持健康的心脏老化。我们的初步数据表明，PRC 2组分的功能降低， 防止心脏老化。重要的是，当苍蝇用抗衰老药物治疗时， H3 K27 me 3甲基转移酶抑制剂EZH 2，类似于脂毒性心肌病的救援， 最近出版的。因此，我们假设，表观遗传修饰-特别是H3 K27 me 3心脏 签名-经历年龄相关的变化，导致心脏基因表达异常和进行性 心脏功能障碍在这里，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，保守的生物学途径，以阐明 （epi）与年龄相关的心脏功能下降的遗传控制，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， 表观遗传分析技术在苍蝇心脏中运行。我们将1）表征基因表达和DNA 通过运行最先进的单核Multiome技术，可在年轻和老年心脏的完全相同的细胞中进行访问 ATAC +基因表达2）研究年龄相关的活性和抑制性组蛋白标记的变化， 果蝇心脏和他们的功能后果使用新的切割和运行技术，和3） 通过果蝇体内靶向筛选确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，我们预计操纵表观遗传调节因子可以改善 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 通过恢复类似基因的基因程序。