Genomic and functional characterisation of cell-type specific epigenetic and genetic mechanisms implicated in human obesity. (360G-Wellcome-219602_Z_19_Z)

Regulation of gene expression by DNA methylation (5mC) in response to genetic and environmental risk factors is considered important to human obesity and type-2 diabetes (T2D) pathogenesis. Yet, difficulty finding causal 5mC changes in humans is limiting downstream clinical applications. I have discovered 5mC changes robustly associated with obesity and their predicted effector genes in human adipocytes. I have then refined these loci and genes using human genomics, cross-species transcriptomics and biological evidence to 3 top candidates for discovery of novel mechanisms of disease – the MEDAG, FGFRL1 and TXNRD1 loci. I will use sophisticated gene targeting to investigate the causal effects of the MEDAG, FGFRL1 and TXNRD1 genes on obesity and T2D in a mouse model of human disease, and detailed phenotyping to examine the pathophysiological mechanisms. In parallel, I will use functional and experimental genomics to explore the regulatory significance of obesity-associated 5mC sites on MEDAG, FGFRL1 and TXNRD1 gene expression, and the underlying epigenetic mechanisms, in human adipocytes. These complementary lines of evidence will establish whether locus-specific 5mC variations and subsequent gene expression changes impact on human obesity phenotypes, and may define epigenomic and molecular targets for new obesity and T2D therapies.