The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated
 p16
 
 INK4a
 
 and
 hMLH1
 Genes

Kondo, Emiko; Gu, Zhaodi; Horii, Akira; Fukushige, Shinichi

doi:10.1128/mcb.25.11.4388-4396.2005

Cited by 101 publications

(75 citation statements)

References 36 publications

(46 reference statements)

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“…Although MBD4 is mainly related to DNA repair mechanism, it is also involved in methylation-dependent transcriptional repression of p16 INK4a and MLH1 genes (Kondo et al, 2005).…”

Section: Mbd4mentioning

confidence: 99%

Proteins that bind methylated DNA and human cancer: reading the wrong words

2008

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DNA methylation and the machinery involved in epigenetic regulation are key elements in the maintenance of cellular homeostasis. Epigenetic mechanisms are involved in embryonic development and the establishment of tissue-specific expression, X-chromosome inactivation and imprinting patterns, and maintenance of chromosome stability. The balance between all the enzymes and factors involved in DNA methylation and its interpretation by different groups of nuclear factors is crucial for normal cell behaviour. In cancer and other diseases, misregulation of epigenetic marks is a common feature, also including DNA methylation and histone posttranslational modifications. In this scenario, it is worth mentioning a family of proteins characterized by the presence of a methyl-CpGbinding domain (MBDs) that are involved in interpreting the information encoded by DNA methylation and the recruitment of the enzymes responsible for establishing a silenced state of the chromatin. The generation of novel aberrantly hypermethylated regions during cancer development and progression makes MBD proteins interesting targets for their biological and clinical implications. British Journal of Cancer (2008) DNA METHYLATION AND ITS MEDIATORSDNA methylation is one of the most important mechanisms for epigenetic silencing in mammals. It is a key element in heterochromatin formation and maintenance, and is involved in processes such as X-chromosome inactivation and gene imprinting. DNA methylation also occurs at repetitive sequences to ensure chromosome stability. DNA methylation is developed by a family of DNA methyltransferase enzymes (DNMTs) that add a methyl group to the fifth carbon position of cytosine when followed by a guanine nucleotide. Methylation of DNA is accompanied by histone post-translational modifications that modulate DNA function, regulating chromatin structure and determining the transcriptional state of the DNA wrapped around it.The crosstalk between DNA methylation and histone modifications is established by different nuclear factors. Among them, it is particularly remarkable a family of proteins that contain a MethylCpG-binding domain commonly known as MBD proteins that recognises single methylated CpG dinucleotide (Hendrich and Bird, 1998). MBD family members recruit histone modifying and chromatin remodeling complexes to methylated sites. The MBD family of proteins is composed by five members namely MeCP2, MBD1, MBD2, MBD3 and MBD4. MeCP2 was the first characterised member and its 70 amino acids region corresponding to the MBD was used for database identification of the remaining MBD containing proteins. The binding affinity of MBD proteins differs between them, as was demonstrated that MBD2 is the MBD protein with higher methylated DNA-binding affinity in vitro .

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“…Although MBD4 is mainly related to DNA repair mechanism, it is also involved in methylation-dependent transcriptional repression of p16 INK4a and MLH1 genes (Kondo et al, 2005).…”

Section: Mbd4mentioning

confidence: 99%

Proteins that bind methylated DNA and human cancer: reading the wrong words

2008

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“…All of these proteins are involved in the transcriptional repression of methylated DNA (19,20). The methyl-CpG binding domain protein 2 (MeCP2) can interact with both the corepressor SinA 3 and histone deacetylases (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Methyl-CpG Binding Domain Proteins and Their Involvement in the Regulation of the MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 Gene Promoters

Wischnewski¹,

Friese

Pantel³

et al. 2007

Molecular Cancer Research

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Promoter hypermethylation is responsible for the restricted expression of the tumor-associated MAGE antigens. In order to elucidate the mechanism underlying methylation-dependent repression, we examined the involvement of methyl-CpG binding proteins, MBD1, MBD2a, and MeCP2, in silencing of MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 genes. Electrophoretic mobility shift assays displayed binding of MBD1 to the methylated and unmethylated MAGE-A promoters. Using chromatin immunoprecipitation assays, in vivo binding of MBD1 and MeCP2 to the promoters could be observed in MCF-7 and T47D cells. Transient transfection assays of MCF-7 cells were done with the transcriptional repression domains (TRD) of MBD1, MBD2a, and MeCP2, and MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 promoters. Whereas the TRD of MBD1 and MeCP2 repressed the MAGE-A promoters, the TRD of MBD2 had no inhibiting effect on the promoter activity. Furthermore, cotransfections of Mbd1-deficient mouse fibroblasts and MCF-7 cells with MBD2a, MeCP2, and the MBD1 splice variants, 1v1 and 1v3, showed that strong methylation-dependent repression of the MAGE-A promoters could not be further down-regulated by these proteins. However, the two MBD1 splice variants, 1v1 and 1v3, were able to repress the basal activity of unmethylated MAGE-A promoters. Additional cotransfection experiments with both isoforms of MBD1 and the transcription factor Ets-1 showed that Ets-1 could not abrogate the MBD1-mediated suppression. In contrast with the repressive effect mediated by MBD1, MBD2a was found to up-regulate the basal activity of the promoters.In conclusion, these data show, for the first time, the involvement of methyl-CpG binding domain proteins in the regulation of the MAGE-A genes.

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“…Since MBDs bind 5mC but not 5hmC (9), Tet-mediated conversion of 5mC ¡ 5hmC limits the binding of MBDs, and potentially MBD-binding partners, such as DNMT3b, to facilitate passive demethylation. In addition, Tet-mediated generation of 5hmC has also been proposed to initiate a base excision repair process that results in demethylation (12).…”

mentioning

confidence: 99%

“…DNMT3a and DNMT3b mediate de novo DNA methylation, whereas DNMT1 acts on newly synthesized DNA to maintain methylation marks (21). Transcription may be limited by an effect of promoter methylation itself to reduce the affinity for trans-activating factors and by methyl-CpG binding domain (MBD) proteins, which recognize 5=-methylated cytosine (5mC) residues, recruiting transcriptional repressors or chromatin modifiers to these sites (16) and stearically hindering transcription factor binding (12). Moreover, DNMT3b and MBD4 have been shown to physically and functionally interact in a complex with negative vitamin D response elementbinding protein to initiate and maintain methylation of the cytochrome P-450 (CYP)27B1 promoter (10).…”

mentioning

confidence: 99%

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

Kong

Kone

2013

American Journal of Physiology-Renal Physiology

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Yu Z, Kong Q, Kone BC. Aldosterone reprograms promoter methylation to regulate ␣ENaC transcription in the collecting cuct. Am J Physiol Renal Physiol 305: F1006 -F1013, 2013. First published August 7, 2013 doi:10.1152/ajprenal.00407.2013.-Aldosterone increases tubular Na ϩ absorption largely by increasing ␣-epithelial Na ϩ channel (␣ENaC) transcription in collecting duct principal cells. How aldosterone reprograms basal ␣ENaC transcription to high-level activity in the collecting duct is incompletely understood. Promoter methylation, a covalent but reversible epigenetic process, has been implicated in the control of gene expression in health and disease. We investigated the role of promoter methylation/demethylation in the epigenetic control of basal and aldosterone-stimulated ␣ENaC transcription in mIMCD3 collecting duct cells. Bisulfite treatment and sequencing analysis after treatment of the cells with the DNA methyltransferase (DNMT) inhibitor 5-aza-2=-deoxycytidine (5-Aza-CdR) identified clusters of methylated cytosines in a CpG island near the transcription start site of the ␣ENaC promoter. 5-Aza-CdR treatment or small interfering RNA-mediated knockdown of DNMT3b or methyl-CpG-binding domain protein (MBD)-4 derepressed basal ␣ENaC transcription, indicating that promoter methylation suppresses basal ␣ENaC transcription. Aldosterone triggered a time-dependent decrease in 5mC and DNMT3b and a concurrent enrichment in 5-hydroxymethylcytosine (5hmC) and ten-eleven translocation (Tet)2 at the ␣ENaC promoter, consistent with active demethylation. 5-AzaCdR mimicked aldosterone by enhancing Sp1 binding to the ␣ENaC promoter. We conclude that DNMT3b-and MBD4-dependent methylation of the ␣ENaC promoter limits basal ␣ENaC transcription, in part by limiting Sp1 binding and trans-activation. Aldosterone stimulates the dispersal of DNMT3b and recruitment of Tet2 to demethylate the ␣ENaC promoter to induce ␣ENaC transcription. These results disclose a novel epigenetic mechanism for the control of basal and aldosterone-induced ␣ENaC transcription that adds to previously described epigenetic controls exerted by histone modifications. epigenetic; chromatin; transcription factor; methylcytosine; methyltransferase; epithelial Na ϩ channel THE EPITHELIAL NA ϩ CHANNEL (ENaC) mediates Na ϩ entry across the apical membranes of salt-absorbing epithelia of the kidney, distal colon, and lung and functions as the rate-limiting step in active transepithelial Na ϩ and fluid absorption. In serving this role, ENaC plays important roles in the regulation of extracellular fluid volume and blood pressure (1,20). Of the three ENaC subunits (␣, ␤, and ␥), ␣ENaC appears to be critical to the overall salt balance, as evidenced by the finding that mice with targeted inactivation of ␣ENaC in the connecting tubule (CNT)/collecting duct (CD) exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype (5). ␣ENaC is also a molecular target of aldosterone, which stimulates its transcription in a manner that is rate l...

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The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16 ^INK4a and hMLH1 Genes

Cited by 101 publications

References 36 publications

Proteins that bind methylated DNA and human cancer: reading the wrong words

Proteins that bind methylated DNA and human cancer: reading the wrong words

Methyl-CpG Binding Domain Proteins and Their Involvement in the Regulation of the MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 Gene Promoters

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

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The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16 INK4a and hMLH1 Genes

Cited by 101 publications

References 36 publications

Proteins that bind methylated DNA and human cancer: reading the wrong words

Proteins that bind methylated DNA and human cancer: reading the wrong words

Methyl-CpG Binding Domain Proteins and Their Involvement in the Regulation of the MAGE-A1, MAGE-A2, MAGE-A3, and MAGE-A12 Gene Promoters

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

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The Thymine DNA Glycosylase MBD4 Represses Transcription and Is Associated with Methylated p16 ^INK4a and hMLH1 Genes