Time-resolved cartography of the hepatic methylome and transcriptome during type 2 diabetes pathogenesis

Type 2 diabetes (T2D) is associated with epigenetic alterations in many disease relevant organs. However, it remains unclear if the dysregulated epigenome causally contributes to diabetes pathology. Moreover, it needs to be better understood if diabetogenic epigenetic marks can be acquired in differentiated cells during a life time as opposed to in utero programming and epigenetic inheritance. This proposal aims to investigate the time-resolved hepatic methylome and transcriptome by whole genome bisulphite sequencing (WGBS) and RNA sequencing (RNA-seq) in liver during induction of insulin resistance. Mice are fed with high-fat diet to induce diet-induced obesity and insulin resistance for 1, 2, 4 and 5 weeks (n=5/group). Chow-fed mice serve as a control group. Metabolic parameters including glucose tolerance, body weight, plasma insulin and hepatic triglycerides are monitored. Thereby it can be tackled which diet-induced changes in the hepatic methylome occur before manifestation of insulin resistance. In parallel the hepatic methylome and transcriptome of 36 obese T2-diabetic and 60 obese non-diabetic subjects will be analysed by WGBS and RNA-seq. Comparison of the longitudinal murine and cross-sectional human data will identify genes and epigenetic marks that are causally involved in T2D aetiology and that could play an important role in the human T2D pathology.