Identification of human imprint regulatory regions associated with obesity in children

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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. However, epigenetic regions that alter obesity risk are still unknown. We lack a screening tool for comprehensive measurement of epigenetic modifications, and the ability for 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. First, 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 vary by age. Second, measurements made in the peripheral cell types accessible from otherwise healthy individuals do not always correlate with those of cell types that contribute to obesity, as methylation is known to vary by cell and tissue types. Third, alteration to epigenetic marks can be caused by obesity, and this temporal ambiguity between exposure and outcome complicates causal inference. 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. Monoallelic expression of imprinted genes is regulated by parent of origin specific DNA methylation at imprint control regions (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 similar, regardless of cell type, individual, and age. These unique features of ICRs provide a great opportunity for epigenetic studies of disease. To overcome the current obstacles to such studies, we will comprehensively identify regulatory DNA methylation for imprinted genes, creating the first draft of the “imprintome”. The comprehensive identification ICRs is necessary, because while as many as 400 genes have been predicted to be imprinted, only ~30 ICRs regulating 70-80 genes are known. Our overarching goal is to use genome-wide 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 that differential methylation which is consistent across cell type, sex, and age – the hallmark of an ICR. The imprintome panel will then be evaluated in relation to obesity, to correlate methylation in umbilical cord blood to the onset of obesity later in childhood. Complete identification of altered imprint regulation will provide markers for prospective risk assessment, identify mechanisms contributing to obesity development, and inform future work into environmental exposures affecting obesity. This assay would also then be applicable to any disease or exposure, creating new opportunities for understanding these conditions.