Kurzfassung

It is becoming clear that epigenetic alterations such as aberrant DNA methylation and histone acetylation contribute directly to liver diseases, including cancer development and progression. The research of my group is focused on the molecular mechanisms involved in the development of liver diseases, how hepatocytes interact with immune cells during disease and how to modulate these interactions for therapy. In recent investigations we studied the pathophysiological roles of Sirtuins, the...It is becoming clear that epigenetic alterations such as aberrant DNA methylation and histone acetylation contribute directly to liver diseases, including cancer development and progression. The research of my group is focused on the molecular mechanisms involved in the development of liver diseases, how hepatocytes interact with immune cells during disease and how to modulate these interactions for therapy. In recent investigations we studied the pathophysiological roles of Sirtuins, the mammalian homologs of the yeast histone deacetylase Sir2 in liver diseases. We could show that the immunosuppressive pregnancy hormone, chorionic gonadotropin (HCG), regulates the longevity proteins FOXO3a and SIRT1 leading to a therapeutic impact on acute and chronic inflammatory liver injury. Sirt6, a NAD-dependent deacetylase of the sirtuin gene family is highly expressed in hepatocytes. Its ablation in mice causes liver dysfunction and a pronounced premature aging phenotype. We investigated Sirt6 expression in over 200 primary human liver cancers, normal and cirrhotic livers using gene array data and further analyzed gene expression signatures we generated from isolated hepatocytes of Sirt6 KO mice in this data set. We could show that the Sirt6-KO hepatocyte signature clustered primary HCC patients into two subgroups with significantly different disease outcome. Among the prognostically-relevant signature genes were circadian clock genes (Rev-Erbalpha, Bmal1, Per1, Cry1 and Cry2). Further comparison of these genes in Sirt6-deficient and wildtype mouse livers confirm deregulated expression patterns in the circadian timing system. In our project we will analyze the molecular function of Sirt6 in the regulation of these genes in hepatocytes» weiterlesen» einklappen