Epigenetic drift of the Aging Heart in Drosophila

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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.