Area of Expertise: Regulation of DNA methylation in development and disease
DNA methylation is a heritable and reversible epigenetic phenomenon which is associated largely with gene repression. The expression of a large cohort of genes is dynamically regulated during normal cell differentiation, cancer progression and as a result of an exposure to environmental toxins. This change in expression is mediated by changes in the epigenetic state of these genes. Thus, inspection of the regulation of epigenetic processes like DNA methylation is the key to understanding cellular differentiation, developmental origin of disease and recently emphasized transgenerational inheritance.
My lab is interested in understanding the regulation of DNA methylation during stem cell differentiation and mis-regulation in cancer cells. In mammals, DNA methylation is catalyzed by the enzymes called DNA methyltransferases (MTases) Dnmt1, Dnmt3a and 3b. Dnmt3a and 3b are highly expressed in embryonic stages and in embryonic stem (ES) cells. Using mouse ES cells as a model system, we ask the following questions:
How are the targets of DNA MTases specified?
How is tissue-specific expression and splicing of DNA MTases regulated?
What are the roles of major and minor isoforms of Dnmt3b?
These questions are addressed by identifying the protein complexes that interact with DNA MTases and by designing experiments that elucidate the communication between various histone modifications and DNA methylation during the differentiation of stem cells. The possible role of RNA mediated targeting of DNA MTases is another subject of investigation.
My lab has an ongoing interest in the insulator protein Vezf1, which regulates the expression and splicing of Dnmt3b in mouse ES cells. My previous studies in Vezf1 -/- ES cells have shown widespread loss of DNA methylation, including at CpG islands, in the vicinity of several tissue specific genes that regulate developmental programs. New studies are investigating the sites that lost methylation in Vezf1 -/- ES cells as specific targets of Dnmt3b.
It has been speculated that changes in the composition of DNA MTase protein complexes could result in altered specificity of DNA methylation in cancer cells. It is planned to perform a comparative proteomics analysis to discover protein complexes that associate with MTases in normal vs. cancer cells. These studies will lead us to further investigate the mechanisms that cause altered specificity of DNA methylation in cancer cells.