Solving the Mysteries of Epigenetics and Unmasking the Link Between Metabolism and Gene Expression

My laboratory focuses on the transcriptional regulation of cancer related genes including oncogenes and tumor suppressor genes. Specifically, we are studying the molecular mechanisms by which aberrant cytosine methylation of CpG dinucleotides affects gene expression during the development of cancer. We have focused primarily on the tumor suppressor gene SOD2 that encodes the antioxidant enzyme superoxide dismutase. We have determined that site specific DNA methylation of the SOD2 gene promoter can suppress its transcriptional activation. Thus, cytosine methylation of genetic regulatory elements within this important tumor suppressor gene can mediate its inactivation. We are also studying transcription factor AP-2 and its interactions with the SOD2 promoter. Interestingly, these interactions are affected by DNA methylation. We are also assessing chromatin accessibility in the region of the SOD2 promoter in cells that differentially express the gene. Our future research directions will be aimed at elucidating the role of cytosine methylation as a mechanism for inactivation of other genes involved in protection against oxidative damage as well as other classical tumor suppressor genes, and to elucidate the mechanism(s) by which CpG methylation can bring about these changes in gene expression.

We have recently become interested in the mechanisms underlying transcriptional repression of another tumor suppressor gene important to human mammary cancer, maspin. We have shown that maspin is frequently silenced by an epigenetic mechanism invlving DNA methylation and histone hypoacetylation of the maspin 5' regulatory region. Our future studies will involve additional studies on these and other tumor suppressors, and dissect the molecular mechanisms underlying how epigenetic changes modulate gene expression in cancer.