Abnormal expression of Dnmt1 in vivo induces cellular alterations such as transformation, and an increase in Dnmt1 mRNA plays a causal role in c-fos-, ras- and SV40 large T antigen-induced transformation of fibroblasts in vitro. Here, we have investigated the regulation of Dnmt1 transcription. We identified the promoter region and major transcription start sites of mouse Dnmt1 and found two important cis-elements within the core promoter region. One is an E2F binding site, and the other is a binding site for an as yet unidentified factor. Point mutations in the two cis-elements decreased promoter activity in both non-transformed and transformed cells. Thus, both sites play a critical role in regulation of Dnmt1 transcription in proliferating cells. Treatment with trichostatin A, a specific inhibitor of histone deacetylase, increased Dnmt1 promoter activity in G0/G1-arrested NIH 3T3 cells. Furthermore, the decrease in promoter activity induced by expression of E2F-1 and Rb was reversed by trichostatin A treatment of Saos-2 cells. Taken together, these data indicate that transcription of Dnmt1 is regulated in a complex fashion by E2F and other transcription factors through E2F-Rb-HDAC-dependent and -independent pathways. These findings suggest that Dnmt1 is a target gene of these pathways in cell proliferation, cell transformation and tumorigenesis.
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