This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cytosine methylation of chromosomal DNA represents a heritable epigenetic mechanism to control gene transcription. This mechanism is deregulated in virtually all human tumors frequently leading to promoter hypermethylation of tumor suppressor genes and their transcriptional silencing. Inhibition of DNA methylation machinery resulting in re-expression of these genes in tumor cells therefore represents an attractive possibility for anticancer therapies. However, nature of signals governing the generation of aberrant DNA methylation patterns in tumors is poorly understood, thus hampering our effort to design more efficient therapeutic strategies. Three DNA methyltransferases ?DNMT1, DNMT3A and DNMT3B ?are thought to generate and maintain DNA methylation patterns during normal development and in cancer. A relative contribution of individual enzymes to global methylation patterns in tumors has not been addressed to date. To understand the role of DNA methyltransferases in generating aberrant methylation landscape during tumorigenesis, this research proposal will focus on genome-wide analysis of DNA methylation in mouse lymphomas deficient for DNA methyltransferases:
Specific Aims of this proposal are: 1.) To dissect functions of DNA methyltransferases in normal and malignant hematopoiesis utilizing mouse transgenic and knockout models and global genome-wide approaches. 2.) To test the feasibility of targeting individual enzymatic activities of Dnmts (Dnmt1, Dnmt3a, Dnmt3b and their targets) for anti-cancer therapies. 3.) To understand mechanistically the cooperation of DNA methylation with histone modifications in regulation of transcription in normal and tumor setting. Altogether, these studies will elucidate the role of Dnmt1, Dnmt3a and Dnmt3b in mouse hematopoiesis and lymphomagenesis and will substantially enhance our understanding of epigenetic events governing transcriptional regulation.
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