Molecular Mechanisms of Aberrant DNA Methylation
The research interests of my laboratory focus on the epigenetic basis of human carcinogenesis. Aberrant gene silencing resulting from alterations in DNA methylation and chromatin structure play an important role in the inactivation of tumor suppressor genes in human cancers. We use a number of approaches ranging from the detailed molecular analyses of individual genes, to tumor biology and functional genomics, to investigate the molecular mechanisms underlying these gene silencing events, and how the epigenetic silencing of certain genes contributes to human carcinogenesis. Our studies of TMS1/ASC, a gene identified in our lab that is methylated and silenced in human breast and other cancers indicate that local chromatin architecture and the presence of specific histone modifications plays a critical role in normal, and abnormal DNA methylation patterning. Functional studies have revealed a role for TMS1 in apoptotic signaling, and in particular, the ability of normal breast epithelial cells to undergo programmed cell death in response to loss of extracellular matrix contacts. It is our hypothesis that epigenetic silencing of TMS1 provides a mechanism for such cells to resist apoptosis, a critical step in early breast cancer development.
Computational Study of Methylation Susceptibility
A recent focus of our lab is to combine genome-wide methylation studies with bioinformatics to ask why certain genes are targets of epigenetic gene silencing in cancer. We have demonstrated that one aspect driving the aberrant methylation of certain gene loci is an underlying susceptibility dictated by local sequence context. We are developing computational models based on DNA sequence features that are capable of predicting genes that are prone to aberrant methylation in cancer cells. The further refinement of such models will ultimately allow the identification of local sequence/structural features that contribute to the risk of aberrant methylation. Moreover, the ability to identify those genes at risk of epigenetic silencing will provide novel molecular targets for further study as potential biomarkers for improved cancer diagnosis and treatment planning.
