The influence of germline chromatin state on somatic fat metabolism and longevity

Stanford University, Stanford CA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): The goal of this proposal is to understand how germline chromatin state impacts somatic fat metabolism and lifespan. Altering chromatin state regulation can extend lifespan in many model organisms, but the mechanisms by which epigenetic modifications can delay aging are largely unknown. An interesting possibility is that altered chromatin state in one tissue elicits systemic effects to influence aging. In the nematode C. elegans, deficiencies in the COMPASS histone methyltransferase complex, which promotes trimethylation of lysine 4 on histone 3 (H3K4me3), extend lifespan by acting in the germline. Preliminary data generated in the Brunet lab indicate that altered germline H3K4me3 regulation in the germline also induces the accumulation of monounsaturated fatty acids in somatic tissues such as the intestine. These observations raise the exciting possibility that chromatin state in the germline can signal to and impact fat metabolism in other tissues. Although some signaling pathways linking germline loss to fat metabolism have been identified, mechanisms that specifically communicate germline chromatin state to somatic tissues have not been studied. This work will challenge the dogma that high fat is always associated with poor health, and will reveal specific lipid types that are beneficial for longevity. Based on preliminary data from the Brunet lab and published studies, I hypothesize that altered H3K4me3 in the germline initiates germline-to-soma signaling via secreted peptides, which induces a fat metabolic switch in the soma, resulting in lifespan extension. Using tissue-specific genetic and biochemical techniques in combination with lipid metabolic profiling, I will: i) determine how altered germline H3K4me3 regulation signals to other tissues, ii) characterize the tissue-specific molecular events that regulate fat accumulation in response to altered germline H3K4me3, and iii) identify how a switch in fat metabolism towards monounsaturated fatty acid accumulation promotes longevity. Because key regulators of fat metabolism are conserved from nematodes to humans, delineating how germline chromatin impacts fat metabolism in this system will likely yield findings that are applicable to other organisms. These studies will also address how specific alterations in fat metabolism are causal in longevity, potentially transforming our understanding of how fat composition and dietary fats can regulate lifespan. Undertaking this research will enhance my scientific and professional development by exposing me to new concepts, techniques, and model systems in the study of aging. This work will set the foundation for my progression towards a career in aging research.