Epigenetic regulation of hepatic gene expression in the pathogenesis of insulin resistance

• Applicant: Professorin Dr. Henriette Kirchner
• Subject Area: Endocrinology, Diabetology, Metabolism ; Gastroenterology
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279373746

Previously I and others showed that type 2 diabetes (T2D) is associated with changes in DNA methylation in liver of obese subjects. However, the precise mechanism how gene expression is regulated by DNA methylation in the diabetic liver and whether these alterations contribute to hepatic insulin resistance remain mostly unknown. My project proposal aims to identify dynamic epigenetic regulation of important metabolic genes in the liver to increase our understanding of insulin resistance and to identify novel therapeutic approaches to reverse the epigenetically altered gene expression programs associated with obesity and T2DM.New aims that are added for the sixth year of finding are:novel 1.1. microRNA expression and WGBS in liver of T2-diabetic obese subjects and DIO micenovel 2.4. Initial metabolic characterization of Galnt18-/- miceDuring the first funding period liver biopsies form obese T2-diabetic and non-diabetic subjects were collected. Furthermore, a longitudinal mouse study was performed in which liver from diet-induced obese mice was harvested 1, 2, 4, 5, 6, 7, 8 and 12 weeks after onset of high-fat feeding. In aims 1.1 analysis of microRNA and whole-genome bisulfide sequencing (WGBS) data will be performed in these human and mouse liver samples to find genes that are epigenetically dysregulated in 2TD and to track if these changes are dynamic and causal for the development of insulin resistance. During the first funding period we already identified that genomic and epigenetic alterations are associated with altered transcription factor binding and T2D in liver. Adding more genome-wide data will elevate the project and guarantee a more efficient identification of epigenetic mechanisms leading to hepatic insulin resistance. Moreover, molecular mechanisms leading to altered DNA methylation will be studied in detail in the expended funding period.Aim 2.4. will characterize the glucose and energy metabolism of Galnt18-deficient mice (Galnt18-/-). GALNT18 is important for formation of glycoproteins but metabolic functions of GALNT18 are currently unknown. Galnt18-/- mice are currently breeding at the local animal facility for colony expansion and first data show that Galnt18-/- mice have reduced blood glucose and plasma-insulin concentrations. The body-weight, food intake, body composition, glucose- and insulin tolerance and energy metabolism will be characterized in these mice under normal and high-fat feeding conditions on a whole-body level. Finding novel diabetes disease genes is of high importance for understanding and diabetes pathogenesis and to develop future treatment strategies.

• DFG Programme: Independent Junior Research Groups