Characterizing the Human Imprint Regulatory Regions Associated with Childhood Obesity

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT The rapid increase in the prevalence of obesity in the last 30 years has led to the hypothesis that epigenetic mechanisms mediate associations between environmental cues and obesity outcomes. Nevertheless, epigenetic regions that alter obesity risk are still largely unknown. We presently lack a screening tool for comprehensive measurement of epigenetic modifications. Such a screen in any disease or exposure of interest would be of great utility for a broad range of human health studies. The interpretation of human epigenetic data generated using genome-scale approaches is hampered by three main obstacles. Firstly, available data are largely based on methylation differences measured in DNA obtained cross-sectionally at different ages throughout the life course, yet DNA methylation marks are known to vary by age. Secondly, although methylation is known to vary by cell and tissue types, measurements are made in accessible peripheral cell types accessible from otherwise healthy individuals, and do not always correlate with those of cell types that contribute to obesity. Thirdly, alteration to epigenetic marks can be caused by obesity, and this temporal ambiguity between exposure and outcome complicates causal inference. To overcome these obstacles, we will comprehensively identify regulatory DNA methylation for imprinted genes, creating the first draft of the human “imprintome”. Epigenetically regulated imprinted genes are estimated to comprise 1-2% (200-400 genes) of the human genome, and are critical in the development of the early embryo; however, only ~30 imprint control regions (ICRs), regulating 70-80 genes, are known. Monoallelic expression of imprinted genes is regulated by parent- of-origin specific DNA methylation at ICRs that is established prior to germ-layer specification and maintained in somatic tissues throughout life. Therefore, methylation marks regulating the expression of these genes are functionally relevant, and are conserved across cell types, among individuals, and throughout aging. These unique features of ICRs provide a means to a comprehensive tool for multiplexed measurement of early acquired epigenetic modifications, and assess their link between exposures and disease. Our overarching goal is to use genomewide approaches to systematically identify all ICRs using a wide variety of samples, including multiple cell types from males and females from a wide age range. In this way, identification can be restricted to only differentially methylated regions (DMRs) that are consistent across cell type, sex, and age – the hallmark of ICRs. The ICR panel will then be evaluated in relationship to obesity, by identifying, in umbilical cord blood at birth, ICR patterns predictive of obesity later in childhood. Identifying altered imprint regulation will provide markers for prospective risk assessment, identify mechanisms contributing to obesity development, and inform future research into environmental exposures affecting obesity. Once developed, this ICR screening assay would also then be used to identify regions of early epigenetic perturbation associated with any disease or exposure, creating new opportunities for understanding the fetal origins of these conditions.