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DNA modification by methylation of the cytosine base is a fundamental epigenetic mechanism by which a range of developmental and cellular processes are regulated. It has been demonstrated that DNA methylation is essential for animal development, since inactivation of a constitutively expressed DNA methylation enzyme Dnmt1 in mice result in embryonic lethality. DNA methylation plays important roles in regulation of gene expression, suppression of viral infection, genomic imprinting and X chromosome inactivation. In recent years, numerous studies have also linked DNA methylation to various types of human cancer. However, the underlying mechanisms by which alterations in DNA methylation promotes cancer formation is large unknown. De novo methylation of unmodified DNA is a developmentally regulated process which is activated in early embryonic cells, but is inert in adult tissues. Aberrant activation of de novo methylation in adult tissues has been associated with transcriptional silencing of tumor suppressor genes in multiple tumors. Recently, a novel family of de novo DNA methyltransferase genes, termed Dnmt3a and Dnmt3b, have been cloned from both human and mouse. The mouse genes are expressed in embryonic stem cells, but weakly in adult somatic tissues. To investigate how Dnmt3 methyltransferases are regulated and what roles they play during mouse development, and to determine whether alterations in DNA methylation or Dnmt3 expression causes cancer, the following specific aims will be pursued. Aim 1: To generate Dnmt3-deficient mice using gene targeting methods and characterize their developmental defects. Aim 2: To analyze Dnmt3 expression during mouse development and identify cis-acting elements that regulate Dnmt3 transcription. Aim 3: To determine whether endogenous Dnmt3 expression is induced by oncogenic transformation, and the effect of Dnmt3 transgene expression on de novo methylation of CpG islands, oncogenic transformation, and tumor formation in nude mice. Aim 4: To evaluate the genetic effects of inactivation or ectopic expression of Dnmt3 in transgenic mice on tumor progression or suppression. The intestinal tumor model, the Min mice, will be used to test whether Dnmt3a and Dnmt3b have a role in intestinal polyp formation like Dnmt1. The molecular and genetic approaches described in this proposal will unravel the biological function of de novo methylation in development and cancer.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.