Kurzfassung

Alcohol consumption can induce epigenetic alterations leading to metabolic dysfunction of the liver and deregulation of the immune system that play an important pathophysiological role in developing alcoholic liver disease (ALD). Although various alcohol-induced epigenetic changes such as alterations in DNA methylation, histone acetylation/methylation and expression of ncRNAs are described, the responsible mechanisms and key epigenetic regulators are not well understood and specific therapies...Alcohol consumption can induce epigenetic alterations leading to metabolic dysfunction of the liver and deregulation of the immune system that play an important pathophysiological role in developing alcoholic liver disease (ALD). Although various alcohol-induced epigenetic changes such as alterations in DNA methylation, histone acetylation/methylation and expression of ncRNAs are described, the responsible mechanisms and key epigenetic regulators are not well understood and specific therapies are lacking.  Interestingly mice deficient in the NAD+-dependent deacetylase Sirtuin 6 (Sirt6) have many common features to ethanol induced liver injury on the cellular and molecular level. Further genome wide changes in several histone marks are observed; indicating dynamic gene regulation changes. In the proposed project we will use human primary hepatocytes and liver cell lines already generated in our lab with a CRISPR/Cas9 mediated Sirt6-deletion to analyze the role of SIRT6 as an epigenetic brake during the pathogenic process of alcoholic liver disease. Because epigenetic alterations are in principle reversible, the modulation of key epigenetic regulators seems a promising strategy to treat alcohol induced metabolic deregulation.
 » weiterlesen» einklappen