Assistant Professor, Eppley InstituteTel: 402-559-5543 (Office)
E-mail: Rene Opavsky
DNA methylation in hematologic malignancies, epigenetics
Summary of Research
DNA methylation in mammalian cells represents an important epigenetic mechanism to control gene expression. The DNA methylation machinery (consisting of methyltransferases Dnmt1, Dnmt3a, and Dnmt3b and accessory proteins) acts in concert with histone-modifying complexes to mediate epigenetic silencing. This finely tuned regulatory mechanism suffers serious insults during tumor development, leaving severe epigenetic scars specific to the genome of the cancer cell manifested by global DNA hypo- and promoter-specific hyper-methylation. Substantial changes in DNA methylation patterns of normal and cancer cells coupled with the fact that DNA methylation is a reversible process makes genes regulated by DNA methylation attractive targets for anticancer therapies.
We previously found that MYC overexpression in mouse model of T cell lymphomas gave rise to a specific signature of DNA hyper-methylation. Inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic hyper-methylation signatures suggesting that aberrant DNA methylation in cancer is driven by the genetic configuration of tumor cells. Our current work focuses on evaluation of specific functions performed by de novo DNA methyltransferases - Dnmt3a and Dnmt3b - during normal hematopoiesis and development of hematological malignancies. Utilizing mouse knockout and knock-in models we test feasibility of targeting individual enzymatic activities of Dnmts (and their targets) for anti-cancer therapies.