Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription

Fuks, François; Burgers, Wendy A.; Godin, N; Kasai, Masataka; Kouzarides, Tony

doi:10.1093/emboj/20.10.2536

Cited by 502 publications

(376 citation statements)

References 51 publications

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“…All of them have been shown to interact directly with the mSin3A-HDACs complex (Robertson et al, 2000;Rountree et al, 2000;Fuks et al, 2001;Datta et al, 2003). In this study, we have revealed that Dnmt3a and Dnmt3b are novel partners of the Ets family transcription factor PU.1.…”

Section: Discussionmentioning

confidence: 76%

“…In vitro translated 35 S-labeled luciferase, CBP1890, MeCP2, Dnmt3a and Dnmt3b were incubated with the 50% slurry of 20 ml of immobilized GST protein and GST-PU.1 fusion protein, and bound proteins were subjected to Nu-PAGE followed by autoradiography. Epigenetic transcriptional repression of PU.1-mediated reporter activity by Dnmt3s Several studies have shown that Dnmt3a and Dnmt3b are associated with HDAC1 and HDAC2 in vivo and in vitro (Robertson et al, 2000;Bachman et al, 2001;Fuks et al, 2001). Histone deacetylase removes the acetyl groups from the amino-terminal of the histone tails, which triggers the assembly of a tightly packed chromatin inaccessible to the transcriptional machinery (Jenuwein and Allis, 2001).…”

Section: Resultsmentioning

confidence: 99%

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Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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“…For example, activation of RAS [MacLeod et al, 1995], down regulation of Rb [Slack et al, 1999], or upregulation of the Wnt signaling pathway [Campbell and Szyf, 2003] leads to increased expression of DNMT1. Certain oncogenes could target DNMT to tumor suppressor genes and thus bring about regional hypermethylation [Fuks et al, 2001;Di Croce et al, 2002;Brenner et al, 2005;Vire et al, 2006]. An interesting possibility is that aberrant DNA methylation of cancer related genes could also come about through activation of signaling pathway by different environmental exposures, which might also include social exposures.…”

Section: Epigenetic Plasticity and Late Onset Pathologymentioning

confidence: 99%

The social environment and the epigenome

Szyf

McGowan

Meaney

2007

Environ and Mol Mutagen

456

222

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The genome is programmed by the epigenome. Two of the fundamental components of the epigenome are chromatin structure and covalent modification of the DNA molecule itself by methylation. DNA methylation patterns are sculpted during development and it has been a long held belief that they remain stable after birth in somatic tissues. Recent data suggest that DNA methylation is dynamic later in life in postmitotic cells such as neurons and thus potentially responsive to different environmental stimuli throughout life. We hypothesize a mechanism linking the social environment early in life and long-term epigenetic programming of behavior and responsiveness to stress and health status later in life. We will also discuss the prospect that the epigenetic equilibrium remains responsive throughout life and that therefore environmental triggers could play a role in generating interindividual differences in human behavior later in life. We speculate that exposures to different environmental toxins alters long-established epigenetic programs in the brain as well as other tissues leading to lateonset disease. Environ. Mol. Mutagen. 49:46-60, 2008. V V C 2007 Wiley-Liss, Inc.

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“…For example DNA methyltransferases are known to independently recruit histone deacetylases, leading to histone deacetylation and transcriptional repression (28,29). In addition, MBDs can independently recruit HDACs to the site of DNA methylation (3,30).…”

Section: Introductionmentioning

confidence: 99%

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

et al. 2007

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tom@pelhamcourt.clara.co.uk Introduction Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative antiproliferative agent oestrogen receptor beta.Methods LNCaP, DU-145 and PC-3 cells were pre-treated with the DNMT inhibitor 5'-aza-2'-deoxycytidine (5-AZAC) for 72 hours followed by 24 hours combined treatment with 5-AZAC and the HDAC inhibitor trichostatin A (TSA). Following treatment, cells were either processed for cell proliferation, cell toxicity, cell viability and apoptosis assays, or harvested for quantitative real-time RT-PCR gene expression analyses. Assessed target genes were oestrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PGR) and prostate specific antigen (PSA). ResultsIn all cell-lines co-treatment with 5-AZAC and TSA was associated with significantly reduced cell proliferation when compared with control groups (p<0.05); associated reduced cell viability and increased cell death was seen in all cases. Caspase activation was significantly increased in the co-treatment group, indicating that apoptosis was a major mechanism of cell death. Most marked effects were seen in the androgen-dependent, AR-positive LNCaP cell-line. In all cell-lines a marked synergistic re-expression of ERβ was identified in the co-treatment group, a finding which was not seen for either AR or PSA. A similar re-expression of PGR was also identified. ConclusionsAt concentrations associated with gene re-expression, the DNA demethylating agent 5-AZAC and the HDAC inhibitor TSA co-operate in an additive and synergistic way to induce apoptosis in prostate cancer cell-lines. Increased apoptosis in the co-treatment group was associated with marked re-expression of ERβ, which is an intriguing finding, raising the possibility of further targeting of prostate cancer cells with ERβ-selective agents such as phytooestrogens and selective oestrogen receptor modulators (SERMs).

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Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription

Cited by 502 publications

References 51 publications

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

The social environment and the epigenome

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

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