Aging is accompanied by large-scale changes in gene expression. Interestingly, environmental interventions that delay aging, such as dietary restriction (DR), can reverse age-associated changes in gene expression. The mechanisms by which DR induces such large-scale changes in gene expression are unclear, although epigenetic control is likely required. Chromatin modification by histone 3 trimethylation at lysine 4 (H3K4me3) is linked with active transcription, whereas trimethylation of histone 3 lysine 27 (H3K27me3) is associated with repression of transcription. However, there is little known concerning the role of histone methylation with respect to aging. Using a directed RNAi screen in C. elegans to ascertain proteins important for longevity, we recently identified members of a multi-protein complex responsible for the trimethylation of H3K4, including the trimethyltransferase SET-2. Furthermore, we found that the knock-down of the H3K27me3 demethylase UTX- 1 prolonged worm lifespan. Our results support the possibility of an orchestrated mechanism of gene regulation critical to organismal lifespan, whereby activating marks (H3K4me3) are simultaneously added to chromatin, as repressive marks (H3K27me3) are removed, to allow coordinate changes in gene expression. Importantly, we have found that at least one member of the H3K4me3 methyltransferase complex, ash-2, functions in the same genetic pathway as one method of DR in C. elegans, raising the intriguing possibility that this particular process of histone methylation may play an important role in longevity in response to DR. To test whether the SET-2 H3K4 trimethyltransferase complex and UTX-1 function coordinately in modulating worm lifespan and to determine the requirement of these proteins for longevity induced by DR, I propose the following specific aims:
Aim 1. To determine whether the SET-2 H3K4 trimethyltransferase complex and UTX-1 play complementary or independent roles in modulating lifespan.
Aim 2. To explore how SET-2 and UTX-1 regulate lifespan in response to DR. Worm genetics and lifespan assays will be used to place utx-1 relative to members of the H3K4 trimethyltransferase complex in longevity and to test the importance of both SET-2 and UTX-1 in longevity induced by different methods of DR in worms. These results will be complemented by an analysis of the levels of H3K4me3 and H3K27me3 in whole worms and in specific tissues. Finally, the generation of fluorescently tagged transgenic lines for SET-2 and UTX-1 will be used for localization in specific tissues and biochemical purification of protein complexes. Long-term goals will be to explore the importance of SET-2 and UTX-1 in the regulation of gene expression during aging. These studies will offer key insight into a conserved mechanism by which aging is regulated, and may ultimately suggest ways to slow aging and prevent age-related diseases.

Public Health Relevance

We recently identified several proteins that are responsible for an important chromatin modification, called histone methylation, also regulate lifespan in C. elegans. These proteins and their functions are highly conserved in more complex animals, including humans. Thus our continued research may ultimately uncover ways to slow aging and/or prevent age related diseases, such as diabetes and cancer.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F05-C (20))
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Finkelstein, David B
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Stanford University
Schools of Medicine
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Maures, Travis J; Booth, Lauren N; Benayoun, Berenice A et al. (2014) Males shorten the life span of C. elegans hermaphrodites via secreted compounds. Science 343:541-4
Greer, Eric L; Maures, Travis J; Ucar, Duygu et al. (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479:365-71
Maures, Travis J; Greer, Eric L; Hauswirth, Anna G et al. (2011) The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell 10:980-90