Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Genomic imprinting is an epigenetic mechanism that modifies gene expression in a manner that is dependent on parental origin. Some estimates suggest that as many as 3% of genes show evidence of imprinting. however the true extent of imprinting in mammals remains unknown. Many imprinted genes play important roles in development, and there is now good evidence that imprinting also contributes towards the common diseases such as cancer, diabetes and metabolic syndrome. The identification of imprinting is therefore important for the proper understanding of genome function in relation to disease. I propose a research plan that utilizes a variety of complementary strategies to identify parent of origin effects at both the DNA and RNA level using studies of human and mouse. Our three specific aims are: i) Perform comparative DNA methylation profiling in a cohort of 113 patients with uniparental disomy (UPD). Patients with UPD provide a unique system that allows the isolated study of DNA derived from a single parent, representing a powerful system for the detection of differentially methylated regions. These data will provide a genome-wide map of loci that show parent-of origin specific methylation in human. ii) Utilize a novel genome-wide association study approach that utilizes SNP genotype and gene expression data in trios to identify imprinted regulatory elements. We will perform RNAseq studies of 150 offspring from HapMap trios for which genome-wide SNP data are available. These studies will allow genome- wide detection of regulatory elements that show parent of origin biases on gene expression. iii) Perform deep RNA sequencing and whole-genome bisulfite sequencing in three different adult and fetal tissues types isolated from F1 hybrid mice produced by reciprocal C57/Bl6 and Mus castaneus matings. These F1 hybrids represent an in vivo model in which there is a high heterozygosity rate across the genome, with each variant of defined parental origin, therefore representing a powerful system for detecting imprinting. These data will enable the comprehensive assessment of both imprinted gene expression and differential methylation marks in multiple tissue types. These studies will produce a comprehensive map of parent of origin effects in the mammalian genome, providing a strong basis for future studies of the effects of imprinting in many human diseases.
Although humans inherit one copy of each gene from each of their parents, the functioning of these genes can vary depending on whether they are inherited from the mother or father. Many of these 'imprinted'genes play important roles in human development and diseases such as diabetes and cancer, but are currently poorly understood. We propose a number of different studies in both mouse and human to identify imprinted genes and their effects on gene expression, which will pave the way for a fuller understanding of the role of parental origin of genes on human development and disease risk.
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|Watson, Corey T; Szutorisz, Henrietta; Garg, Paras et al. (2015) Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure. Neuropsychopharmacology 40:2993-3005|
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|Kappil, Maya A; Green, Benjamin B; Armstrong, David A et al. (2015) Placental expression profile of imprinted genes impacts birth weight. Epigenetics 10:842-9|
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