Carcinogenesis is characterized by the accumulation of multiple genetic and epigenetic changes in cancer cells. De novo methylation of CpG islands which are generally not methylated on autosomal genes in normal cells, is one of the most common genomic alterations in human cancers and occurs in parallel with a genome wide demethylation during carcinogenesis. The aberrant methylation of CpG islands, if it occurs in promoter regions, contributes to the inactivation of tumor suppressor, growth regulatory and DNA repair genes. Epigenetic modification of CpG islands is now considered to be a significant contributor to gene inactivation during carcinogenesis. The objectives of this proposal are to determine the underlying molecular mechanisms for this abnormal de novo methylation using new quantitative methods developed in this laboratory and to take advantage of new discoveries of DNA methyltransferase enzymes, which may play important roles in this process. This will be achieved by the accomplishment of four specific aims in which we will first investigate the relationship between transcription and de novo methylation and test the hypothesis that transcription through a CpG island may facilitate de novo methylation. To probe further the relationship between transcription and de novo methylation, we will investigate the chromatin structure of CpG islands within promoters and downstream of promoters with specific emphasis on the state of histone acetylation. We will also characterize the potential roles of newly described putative de novo methyltransferases in human cancer, and test the effects of overexpression of these enzymes and the effects of nullifying their activities by antisense approaches. The successful achievements of these specific aims will allow us to gain a better understanding of the mechanisms of de novo methylation as they pertain to transcription, influences on chromatin structure and the role of the new DNA methyltransferase enzymes in human carcinogenesis.
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