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Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways.

ABSTRACT: 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.

SUBMITTER: Kimura H

PROVIDER: S-EPMC162240 | biostudies-literature | 2003 Jun

REPOSITORIES: biostudies-literature

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Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways.

Kimura Hiromichi H Nakamura Takahisa T Ogawa Tomoya T Tanaka Satoshi S Shiota Kunio K

Nucleic acids research 20030601 12

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 bin ...[more]

PMID: 12799438

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Project description:Epstein-Barr virus (EBV) was discovered as the first human tumor virus more than 50 years ago. EBV infects more than 90% of the human population worldwide and is associated with numerous hematologic malignancies and epithelial malignancies. EBV establishes latent infection in B cells, which is the typical program seen in lymphomagenesis. Understanding EBV-mediated transcription regulatory networks is one of the current challenges that will uncover new insights into the mechanism of viral-mediated lymphomagenesis. Here, we describe the regulatory profiles of several cellular factors (E2F6, E2F1, Rb, HDAC1, and HDAC2) together with EBV latent nuclear antigens using next-generation sequencing (NGS) analysis. Our results show that the E2F-Rb-HDAC complex exhibits similar distributions in genomic regions of EBV-positive cells and is associated with oncogenic super-enhancers involving long-range regulatory regions. Furthermore, EBV latent antigens cooperatively hijack this complex to bind at KLFs gene loci and facilitate KLF14 gene expression in lymphoblastoid cell lines (LCLs). These results demonstrate that EBV latent antigens can function as master regulators of this multisubunit repressor complex (E2F-Rb-HDAC) to reverse its suppressive activities and facilitate downstream gene expression that can contribute to viral-induced lymphomagenesis. These results provide novel insights into targets for the development of new therapeutic interventions for treating EBV-associated lymphomas.IMPORTANCE Epstein-Barr virus (EBV), as the first human tumor virus, infects more than 90% of the human population worldwide and is associated with numerous human cancers. Exploring EBV-mediated transcription regulatory networks is critical to understand viral-associated lymphomagenesis. However, the detailed mechanism is not fully explored. Now we describe the regulatory profiles of the E2F-Rb-HDAC complex together with EBV latent antigens, and we found that EBV latent antigens cooperatively facilitate KLF14 expression by antagonizing this multisubunit repressor complex in EBV-positive cells. This provides potential therapeutic targets for the treatment of EBV-associated cancers.

Dataset Information

Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways.

Publications

Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways.

Similar Datasets

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