Novel imprint control regions (ICRs) responsive to environmental exposures

PROJECT SUMMARY/ABSTRACT The increased prevalence of obesity in the US and elsewhere 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 largely unknown, and the current lack of a screening tool for comprehensive measurement of epigenetic modifications hampers the identification of associated regions. Such a screen that could also be applied to 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 several obstacles. Firstly, the 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, methylation measurements are made in accessible peripheral cell types accessible from otherwise healthy individuals, and variability of epigenetic marks between cell types means that measurements from these cells do not always correlate with those from cell types that contribute to diseases. Finally, alteration to epigenetic marks can be caused by disease, and this temporal ambiguity between exposure and outcome complicates causal inference. To overcome these obstacles, we have comprehensively identified DNA methylation- controlled regulatory regions for genomically imprinted genes, mapping the first draft of the human “imprint-ome”. 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 ~24 imprint control regions (ICRs), regulating 70 to 80 genes, are presently defined. Monoallelic expression of imprinted genes is regulated by parent-of-origin specific DNA methylation at ICRs that are established prior to germ-layer specification and maintained in somatic tissues throughout life. Our overarching goal is to leverage the newly identified ICRs, to develop a custom platform for measuring them in human specimens, and statistically identify the subset of the human imprint-ome associated with one of the most common trace metals—cadmium, a heavy metal that is sequestered by the placenta, contributing to placental dysfunction. Cadmium related methylation will also be examined in relation to children’s metabolic outcomes. Once developed, this ICR custom platform will be invaluable in identifying regions of developmental epigenetic perturbation associated with other early-acquired diseases or exposures, creating new opportunities for early detection and understanding the fetal origins of human health and disease.