DNA methyltransferase Dnmt1 associates with histone deacetylase activity

Fuks, François; Burgers, Wendy A.; Brehm, Alexander; Hughes-Davies, Luke; Kouzarides, Tony

doi:10.1038/71750

Cited by 877 publications

(612 citation statements)

References 29 publications

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“…These results imply that the action of 5Aza-dC is separate from the induction of promoter demethylation. It is possible that 5Aza-dC disrupts complexes between DNA methyltransferases and histone-modifying proteins [18,19]. Kondo et al [20] have reported that 5Aza-dC dramatically decreases histone H3 Lys-9 methylation, slightly increases Lys-9 acetylation, and moderately increases histone H3 Lys-4 methylation and reactivated gene expression.…”

Section: Discussionmentioning

confidence: 99%

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Murakami¹,

Asaumi²,

Maki³

et al. 2004

Oral Oncology

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Summary Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-Aza-2'-deoxycytidine (5-Aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5Aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5Aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5Aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 hours after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a histone deacetylase inhibitor, in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Murakami¹,

Asaumi²,

Maki³

et al. 2004

Oral Oncology

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“…In humans and mice mutations in the SWI-SNF proteins, which are involved in chromatin remodeling, result in defects in DNA methylation. A growing list of histone modifying enzymes interact with DNMT1, such as HDAC1 and HDAC2, the histone methyltransferases SUV3-9 and EZH2, a member of the multiprotein Polycomb complex PRC2, which methylates H3 histone at the K27 residue [Fuks et al, 2000[Fuks et al, , 2003bRountree et al, 2000;Vire et al, 2006]. DNMT3a was recently also shown to interact with EZH2 which targets the DNA methylation-histone modification multiprotein complexes to specific sequences in DNA [Vire et al, 2006].…”

Section: The Relationship Between Chromatin and Dna Methylationmentioning

confidence: 99%

The social environment and the epigenome

Szyf

McGowan

Meaney

2007

Environ and Mol Mutagen

454

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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“…24,30 Genomic DNA methylation and histone deacetylation are essential but not secluded epigeneticregulating mechanisms. 31 Methylcytosine-binding proteins, which bind to methylated DNA sequences, can recruit HDAC and histone methyltransferases, 32 whereas DNA methyltransferases can directly bind HDAC, representing an interaction between DNA methylation and histone deacetylation. 32,33 Interestingly, TSA alone could result in a more dramatic induction of ASPP1 mRNA expression than 5-aza-dc.…”

Section: Aberrant Expression and Hypermethylation Of Aspp1 In Gestatimentioning

confidence: 99%

“…31 Methylcytosine-binding proteins, which bind to methylated DNA sequences, can recruit HDAC and histone methyltransferases, 32 whereas DNA methyltransferases can directly bind HDAC, representing an interaction between DNA methylation and histone deacetylation. 32,33 Interestingly, TSA alone could result in a more dramatic induction of ASPP1 mRNA expression than 5-aza-dc. Recent studies have discovered that TSA can induce DNA demethylation in some methylated tumorsuppressor genes because of its effect on histone acetylation.…”

Section: Aberrant Expression and Hypermethylation Of Aspp1 In Gestatimentioning

confidence: 99%

Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

et al. 2011

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Gestational trophoblastic disease encompasses a spectrum of trophoblastic lesions including true neoplasms such as choriocarcinomas and the potentially malignant hydatidiform moles, which may develop persistent disease requiring chemotherapy. ASPP1, a member of apoptosis-stimulating proteins of p53 (ASPPs), is a proapoptotic protein that can stimulate apoptosis through its interaction with p53. We evaluated the promoter methylation and expression profiles of ASPP1 in different trophoblastic tissues and its in vitro functional effect on two choriocarcinoma cell lines, namely JEG-3 and JAR. Significant downregulation of ASPP1 mRNA and protein levels was demonstrated in hydatidiform moles and choriocarcinomas, when compared with normal placentas by quantitative-PCR and immunohistochemistry. The ASPP1 mRNA level was significantly correlated with its hypermethylation status, evaluated with methylation-specific PCR, in placenta and gestational trophoblastic disease samples (P ¼ 0.024). Moreover, lower ASPP1 immunoreactivity was shown in hydatidiform moles that progressed to persistent gestational trophoblastic neoplasms than in those that regressed (P ¼ 0.045). A significant correlation was also found between expression of ASPP1 and proliferative indices (assessed by Ki67 and MCM7), apoptotic activity (M30 CytoDeath antibody), p53 and caspase-8 immunoreactivities. An in vitro study showed that ectopic expression of ASPP1 could trigger apoptosis through intrinsic and extrinsic pathways as indicated by an increase in cleaved caspase-9 and Fas ligand protein expression. The latter suggests a hitherto unreported novel link between ASPP1 and the extrinsic pathway of apoptosis. Our findings suggest that downregulation of ASPP1 by hypermethylation may be involved in the pathogenesis and progress of gestational trophoblastic disease, probably through its effect on apoptosis.

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DNA methyltransferase Dnmt1 associates with histone deacetylase activity

Cited by 877 publications

References 29 publications

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

The social environment and the epigenome

Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome

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