It has long been understood that metabolic dysfunction is a common element shared among many different disease states. What is becoming more apparent through many lines of novel research is the role that aberrant epigenetic regulation of gene transcription also plays in these same disease states. The recent discovery of the jumonji domain-containing (jmjC) family of proteins, many of which are capable of oxidatively demethylating lysine and arginine residues on histone tails, illuminates a potential link between the metabolic and epigenetic states of a cell. JmjC proteins may provide mechanistic insight into this dynamic regulation, because they are dependent on several key metabolic determinants for functionality, including Fe(II), ascorbate, 1-ketoglutarate (1KG), and oxygen. This dependence renders them intrinsically susceptible to modulation in cellular metabolism such as those seen in both chronic and acute liver diseases. Given the tremendous importance of metabolic function in hepatocytes and the known aberrations that can occur in disease states such as alcoholic liver disease and hepatitis B infection, the liver represents an ideal model system to further explore the relationship between metabolic function and maintenance of the epigenome. We therefore hypothesize that metabolic perturbation through knockout of Sod2, a critical mitochondrial antioxidant gene, will produce distinct and measurable epigenetic changes at specific gene loci in the murine liver through functional modulation of the jmjC family of histone demethylases under both normal and pathologic circumstances. We propose to pursue the following Specific Aims in order to address this hypothesis: 1) Characterize the functional epigenetic and metabolic impact of Sod2 deletion in murine hepatocytes in vivo. 2) Establish the pathologic synergism of Sod2 knockout in the liver with concomitant chronic alcohol exposure. 3) Evaluate the role of redox perturbation due to Sod2 knockout in a model of alcohol consumption and concomitant chronic hepatitis B viral infection. As epigenetic and metabolic derangements both represent broadly applicable aspects of disease pathogenesis, the proposed studies would contribute significantly to the study of molecular mechanisms of human disease. Moreover, increased familiarity with the proposed techniques, including the handling of cohorts of animals, will contribute to the development of robust research skills and data analysis abilities that the PI will continue to use throughout his career.
By investigating the dynamic interplay between epigenetic and metabolic processes, both of which are significantly altered in many human diseases, the proposed research will contribute to our collective understanding of molecular mechanisms of disease development. This is especially critical for the study of alcoholic liver damage and HBV infection, as the synergism between the two events is not yet well understood, and chronic HBV infection represents a growing health concern worldwide. Moreover, because metabolism is subject to pharmacologic manipulation and epigenetic changes are potentially reversible, the proposed research will ultimately lay the foundation for novel treatment strategies that will impact a broad spectrum of human disease.
| Cyr, Anthony R; Hitchler, Michael J; Domann, Frederick E (2013) Regulation of SOD2 in cancer by histone modifications and CpG methylation: closing the loop between redox biology and epigenetics. Antioxid Redox Signal 18:1946-55 |
| Kulak, M V; Cyr, A R; Woodfield, G W et al. (2013) Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer. Oncogene 32:4043-51 |
