Genetic and Epigenetic Determinants of Longevity

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Project Summary Epigenetic regulation serves as a fundamental mechanism that bridges the genome with the environment, and is a key determinant of longevity. C. elegans uses conserved modes of epigenetic regulation, including histone modifications and non-coding RNAs, has a short normal lifespan and a vast toolkit for molecular and genomic analyses, and represents a powerful model for unraveling the major principles of the epigenetic basis of longevity. The long-term goal of this application is to elucidate how epigenetic regulation bridges the genome and the environment to modulate aging. In this proposal, we build on original discoveries made in our lab and will investigate the mechanistic connection between epigenetic regulation and longevity in C. elegans using three specific aims. In Aim 1, we will investigate the mechanisms by which SET-26, a H3K4me3 reader, regulates DAF-16 transcriptional activity. We recently revealed that SET-26 binds to the histone modification H3K4me3 (histone 3 lysine 4 trimethylation) and requires DAF-16 to modulate stress response and lifespan. In this aim, we will test whether recruitment to H3K4me3 sites in the genome is key for SET-26 functions, and whether SET-26 collaborates with HCF-1 to regulate DAF-16 occupancy at target gene promoters. Our study will illuminate how SET-26 links H3K4me3, a highly conserved histone modification, and DAF-16, a highly conserved master transcription factor, in stress response and aging. In Aim 2, we will elaborate the molecular characteristics and functional consequences of the unique patterns of histone modification changes in aged C. elegans. Ongoing investigations in our lab have revealed interesting patterns of histone modification changes in the somatic cells of aged C. elegans. Specifically, we observed a combined pattern of low H3K36me3 and dynamic H3K4me3, two major histone marks associated with active gene expression, to strongly correlate with RNA expression change with age. We will investigate whether this unique pattern is tissue-specific, correlates with physiological aging, and reflects increased cryptic transcription with age. We will also further characterize the observed gain of the repressive H3K27me3 and heterochromatin H3K9me3 on particular chromosome arms with age. Our study will provide an invaluable resource for the community and will point to the gene regulatory programs key to aging. In Aim 3, we will investigate the epigenetic mechanisms of hormesis in aging. Hormesis in aging, where transient exposure to a mild stress early in life can confer improved vitality later in life, is well known but much remains to be learnt about the molecular basis of its long-lasting beneficial effects. We will compare two stress regiments that have been demonstrated to increase stress resistance, improve proteostasis, and extend lifespan. We will investigate the sustained transcriptional changes that confer the protective effects long after the initial stress exposure, and the chromatin and transcription factors, and possible histone modifications, that regulate the transcriptional memory.