DESCRIPTION (provided by applicant): According to the Developmental Origins of Adult Disease Hypothesis, perturbations in the gestational orearly postnatal environment influence the development of adult diseases. Data from our laboratory and others collectively suggest that this occurs with reprogramming of gene expression via epigenetic changes to the 'histone code'. What constitutes the 'histone code'? While almost all cells of an individual bear near identical genomic constitutions, phenotype is ultimately determined by the gene expression profile. Gene expression is maintained by two major mechanisms: (1) transcription factors and post-transcriptional modifiers, and (2) epigenetic modifications, in particular DNA methylation and core-histone modifications. Research is rapidly demonstrating the importance of the epigenetic code to normal human development as well as the burden of disease that occurs when the epigenetic code or machinery malfunctions. However, it remains a fundamental question in the field of epigenomics research if and how the fetal epigenome varies in response to maternal phenotype and diet modifications, and if it is truly predictive of later in life disease states (suh as obesity and diabetes). Our lab is dedicated to studying the effects of the in utero milieu on epigenetic changes in the fetus. We have developed a non-human primate model of obesity, now in its ninth year, to study the fetal histone code. We have shown that it is maternal high fat diet consumption (rather than maternal obesity per se) which results in abnormal development of both the hypothalamic neurocircuitry and peripheral entrainment integral to regulation of fetal glucose and lipid homeostasis; these alterations are accompanied by epigenetic changes in chromatin structure resulting in reprogramming of fetal gene expression. As a result of this work, we are now uniquely poised to apply concomitantly developed high throughput sequencing technologies with advanced analytical approaches to decipher the molecular means by which the primate epigenome is modified. In this proposal we present our application of these technologies (ChIP-Seq, RNA-Seq, and custom CpG arrays) in our genome wide characterization of the fetal primate hepatic epigenome. Our studies are relevant to public health since they will clarify how the maternal diet influences the developing primate infant, and whether these changes increase the risk of later in life obesity.

Given the growing body of evidence that many (if not the vast majority) of chronic, non-communicable disease have their origins in fetal life, understanding the in utero factors that impact fetal metabolism and development are among the most important public health issues of our time. Our lab is dedicated to studying the effects of the in utero miliu on epigenetic changes in the fetus. We have developed a non-human primate model of obesity, now in its ninth year, to study the fetal histone code. We have shown that it is maternal high fat diet consumption (rather than maternal obesity per se) which results in abnormal development of both the hypothalamic neurocircuitry and peripheral entrainment which regulate fetal glucose and lipid homeostasis; these alterations are accompanied by epigenetic changes in chromatin structure resulting in reprogramming of fetal gene expression. As a result of this work, we are now uniquely poised to apply concomitantly developed high throughput sequencing technologies with advanced analytical approaches to decipher the molecular means by which the primate epigenome is modified.