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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.