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Determine links between SREBPs, SAMe levels and epigenetic regulation

Methylation of histones or DNA affects gene expression at local as well as global levels. The major cellular methyl donor, s-adenosylmethionine (SAMe) is produced by the folate or 1-carbon (1C) cycle. 1CC function may be affected by dietary levels of folate, methionine, choline or betaine, genetic polymorphisms, or alcohol intake, linking potential for epigenetic modification in cancer progression to food intake and metabolism. Physiological limitation of 1CC function has multiple deleterious physiological effects from birth defects to the development of hepatosteatosis and has also been linked to hepatic and colon cancer. While many studies have shown that the availability of methyl donors may dramatically affect human disease, the mechanisms governing SAMe production and epigenetic modification are much less clear. We hypothesize that modulation of SBP-1 function affecting sams-1 expression will also alter methyl group levels and subsequently, histone modification, leading to changes in gene expression relevant to overall nutritional homeostasis. We will determine if modulation of SAMe levels through SBP-1 effects histone methylation at nutritionally important promoters and examine how diet quality and dietary supplementation affect SBP-1 activity by evaluating histone methylation, in addition to employing biological assays for epigenetic changes in gene expression. We will also use unbiased assays such as ChIP-Seq to identify genes whose expression levels are linked to epigenetic changes after sbp-1 RNAi, selecting those with roles in metabolism for further study. These studies will provide a basis for understanding how lipid homeostasis and other dietary influences affect SAMe production and how those are linked to increased lipid accumulation in C. elegans. Future studies will extend these models to mammalian systems to investigate how these changes predispose hepatosteatosis, a component of metabolic syndrome in humans. Figure 2

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