Associate Professor, Eppley InstituteTel: 402-559-5543 (Office)
E-mail: Rene Opavsky
epigenetics, Rb-E2f pathway, lymphomagenesis
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. We are also assessing the importance of cooperation of DNA methylation with histone modifications in hematopoiesis and tumorigenesis. The long-term goal of the laboratory is to get a mechanistic insight into collaborative events governing normal and cancer-specific epigenetic silencing and rigorously assess a potential for therapeutic targeting of molecular players involved in this process.
Our other major area of focus lies in understanding of the role of p16-Rb-E2f pathway in development of lymphomas. Mutations in this pathway are almost ubiquitously found in human cancer. Central to this pathway is Retinoblastoma tumor suppressor (Rb) that along with other ‘pocket’ proteins (p107 and p130) controls cell cycle progression primarily through regulation of E2f transcription factors. The E2f proteins, encoded by eight genes (E2f1-E2f8), regulate cellular proliferation by controlling the transcription of genes involved in DNA replication, DNA repair and mitosis. Utilizing MYC-driven T cell lymphoma model we previously identified E2f2 as a tumor suppressor through its ability to modulate apoptosis. Currently we seek to better understand tumor suppressor role of E2f2 as well as roles of other E2fs in lymphomagenesis. In addition, we also focus on a better understanding of crosstalk between Rb-E2f pathway and DNA methylation that occurs through aberrant methylation of genes involved in the Rb pathway (Rb, p16), transcriptional regulation of Dnmt activity by E2fs, or physical interaction of the Rb protein with DNA methyltransferases.