Mechanisms by which Exendin-4 normalizes epigenetic modifications in IUGR liver

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DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in endocrinology with a research focus on the role of epigenetic gene regulation in diabetes. The candidate is an Assistant Professor in the Department of Pediatrics at the University of Pennsylvania School of Medicine (PENN) and an attending physician at The Children's Hospital of Philadelphia (CHOP). This program is a natural extension of Dr. Pinney's previous work on epigenetic gene regulation in the pancreatic beta cell. She will now focus on the role of epigenetic and epigenomic gene regulation in the liver in the development of diabetes. Rebecca Simmons, M.D., a recognized leader in the field of epigenetics and developmental origins of disease, is an Associate Professor of Pediatrics at PENN and will supervise the training program and serve as Dr. Pinney's primary mentor. The program will be co-mentored by Marisa Bartolomei, Ph.D., Professor of Cell and Developmental Biology at PENN, an established authority in the role of DNA methylation in genomic imprinting and X inactivation in mammalian development. To enhance training, an advisory committee consisting of distinguished scientists with expertise in hepatic glucose metabolism, molecular biology and high- throughput epigenomic analyses have been enlisted to provide guidance. The Division of Endocrinology and the Department of Pediatrics at CHOP and PENN provide a unique combination of resources, core facilities, intellectual expertise and potential collaborations to support a young faculty member. This is an ideal training environment to transition to an independent physician-scientist. A large percentage of K-funded junior faculty at CHOP and PENN go on to receive RO1 funding. Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes (T2DM) in adults. The abnormal intrauterine environment affects the development of the fetus by permanently modifying gene expression in susceptible cells like the hepatocyte. Expression of PPARGC1A (PGC1¿), a transcriptional coactivator that regulates mitochondrial function, is decreased in both humans with T2DM and IUGR rats. Neonatal treatment with Exendin-4 (Ex-4) normalizes PGC1¿ gene expression by restoring USF1 binding and normalizing the IUGR induced epigenetic modifications at the PGC1 ¿ promoter. The central hypothesis is to describe the mechanism by which Exendin-4 normalizes the epigenetic modifications in IUGR liver by restoring the function of the epigenetic initiator USF1. The specific aims include: 1) To determine the mechanism by which Ex-4 reverses epigenetic modifications of PGC1¿ in IUGR liver by investigating the role of USF1 as epigenetic initiator; 2) To determine if USF1 binding is globally responsible for maintaining high levels of histone 3 acetylation and histone 3 lysine 4 methylation, histone marks associated with increased gene transcription at additional hepatic genes critical for regulating hepatic glucose homeostasis. PUBLIC HEALTH RELEVANCE: 23.5 million Americans are estimated to have diabetes and in 2006 diabetes was the 7th leading cause of death in the United States. Intrauterine growth retardation has been linked to the later development of diabetes in adulthood in multiple studies in humans. Studies to determine the underlying molecular mechanisms that lead to the development of type 2 diabetes and interventions aimed and preventing the development of type 2 diabetes will reduce the impact of this major public health burden.