Identifying the molecular mechanisms of transgenerational epigenetic inheritance

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DESCRIPTION (provided by applicant): Longevity is regulated by genetic as well as environmental factors. My recent work has shown that longevity in worms can also be regulated in an epigenetic manner. Mutations of a chromatin regulating complex in the parental generation have a transgenerational epigenetic effect on the longevity of wild-type descendants. However, it is unclear how epigenetic information is inherited from one generation to the next and how this information regulates organismal longevity. My goal in this proposal is to begin to define mechanistically how epigenetic information can be transmitted from parents to descendants to regulate longevity in the nematode C. elegans. Preliminary results suggest that mutation of the histone demethylase SPR-5 provides a second example of transgenerational epigenetic inheritance of longevity. Worms with a mutation in this gene are initially phenotypically normal, however, eventually after many reproductive cycles their descendants lacking the demethylase have progressively longer lifespans. Through a genetic RNAi screen I found that an H3K9 methyl binding protein mediates progressive epigenetic memory of H3K4 demethylation, leading to increasingly reduced fertillity and longer lifespan. The proposed research will help elucidate how an H3K9 methyl binding protein can mediate the effects of an H3K4 demethylase and examine how altered histone modifications can extend longevity. The work proposed here will be conducted in the postdoctoral phase under the mentorship of Dr. Yang Shi, a world leader in chromatin research, who discovered the mammalian homologue of SPR-5, LSD1, as the first histone demethylase. This research funding will help launch an independent research laboratory to study how epigenetic information regulates longevity.