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Maternal Diet Modifies the Fetal Primate Epigenome and Circadian Gene Expression

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Project summary. Accumulating evidence from our laboratory and others suggests that adult diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (an altered "histone code"). Although models of intrauterine growth restriction have been established in rodent models which demonstrate that fetal alterations in the histone code are involved in the persistence and conveyance of the altered postnatal phenotype, little is known about the effects of a high fat (HF) maternal diet and resultant obesity on primate fetal biology. We hypothesized that a HF diet in non- human primates (NHP) would induce tissue specific changes in chromatin structure resulting in altered expression of fetal genes critical to the development of childhood and adult diseases. Based on (1) our preliminary data, and (2) emerging evidence that the Clock family of circadian genes functions to orchestrate multiple metabolic processes, the focus of this proposal is the epigenetic modifications in fetal circadian gene expression induced in response to a HF maternal environment. In Aim 1, we will characterize maternal HF diet-induced chromatin modifications in relevant NHP fetal tissue (hypothalamus and liver). In Aim 2, we will characterize the molecular means by which these chromatin modifications meaningfully alter fetal circadian gene expression. In Aim 3, we will determine if healthful maternal diet modification after chronic HF consumption will revert the overall pattern of the fetal histone code back to its naive state, and if diet improvement alters the epigenetic characteristics and expression of fetal genes of interest in the NHP. Relevance. Obesity causes substantial soical, economic and health burdens. The rate of obesity is escalating disproportionately in children (infants to young adults). This rapid increase is unlikely to be due to environment or genetics alone. Based on previous work, we believe that obestiy in part starts when the child was a fetus in utero and occurs because of reprogramming of gene expression caused by the mother's diet and health. We will test this hypothesis in non-human primates and will determine whether improving maternal diet changes genes of interest that contribute to childhood obesity. Given the obesity epidemic, this has great public health significance.

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