Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vertebrate genomes are heavily methylated at cytosines in the sequence CpG. The biological role of this modification is probably mediated by DNA binding proteins that are either attracted to or repelled by methyl-CpG. MeCP2 is an abundant chromosomal protein that binds specifically to methylated DNA in vitro, and depends upon methyl-CpG for its chromosomal distribution in vivo. To assess the functional significance of MeCP2, the X-linked gene was mutated in male mouse embryonic stem (ES) cells using a promoterless gene-targeting construct containing a lacZ reporter gene. Mutant ES cells lacking MeCP2 grew with the same vigour as the parental line and were capable of considerable differentiation. Chimaeric embryos derived from several independent mutant lines, however, exhibited developmental defects whose severity was positively correlated with the contribution of mutant cells. The results demonstrate that MeCP2, like DNA methyltransferase, is dispensable in stem cells, but essential for embryonic development.
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PMID:The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. 856 62

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity.
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PMID:DNA methyltransferase Dnmt1 associates with histone deacetylase activity. 1061 35

Methylation of CpG islands is associated with transcriptional silencing and the formation of nuclease-resistant chromatin structures enriched in hypoacetylated histones. Methyl-CpG-binding proteins, such as MeCP2, provide a link between methylated DNA and hypoacetylated histones by recruiting histone deacetylase, but the mechanisms establishing the methylation patterns themselves are unknown. Whether DNA methylation is always causal for the assembly of repressive chromatin or whether features of transcriptionally silent chromatin might target methyltransferase remains unresolved. Mammalian DNA methyltransferases show little sequence specificity in vitro, yet methylation can be targeted in vivo within chromosomes to repetitive elements, centromeres and imprinted loci. This targeting is frequently disrupted in tumour cells, resulting in the improper silencing of tumour-suppressor genes associated with CpG islands. Here we show that the predominant mammalian DNA methyltransferase, DNMT1, co-purifies with the retinoblastoma (Rb) tumour suppressor gene product, E2F1, and HDAC1 and that DNMT1 cooperates with Rb to repress transcription from promoters containing E2F-binding sites. These results establish a link between DNA methylation, histone deacetylase and sequence-specific DNA binding activity, as well as a growth-regulatory pathway that is disrupted in nearly all cancer cells.
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PMID:DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. 1088 86

The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.
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PMID:The DNA methyltransferases of mammals. 1100 94

DNA methylation is a major determinant in the epigenetic silencing of genes. The mechanisms underlying the targeting of DNA methylation and the subsequent repression of transcription are relevant to human development and disease, as well as for attempts at somatic gene therapy. The success of transgenic technologies in plants and animals is also compromised by DNA methylation-dependent silencing pathways. Recent biochemical experiments provide a mechanistic foundation for understanding the influence of DNA methylation on transcription. The DNA methyltransferase Dnmt1, and several methyl-CpG binding proteins, MeCP2, MBD2, and MBD3, all associate with histone deacetylase. These observations firmly connect DNA methylation with chromatin modifications. They also provide new pathways for the potential targeting of DNA methylation to repressive chromatin as well as the assembly of repressive chromatin on methylated DNA. Here we discuss the implications of the methylation-acetylation connection for human cancers and the developmental syndromes Fragile X and Rett, which involve a mistargeting of DNA methylation-dependent repression.
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PMID:DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. 1109 25

To evaluate the significance of alterations in DNA methylation during human hepatocarcinogenesis, we examined levels of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and the DNA methylation status in 67 hepatocellular carcinomas (HCCs). The average level of mRNA for DNMT1 and DNMT3a was significantly higher in noncancerous liver tissues showing chronic hepatitis or cirrhosis than in histologically normal liver tissues, and was even higher in HCCs. Significant overexpression of DNMT3b and reduced expression of DNMT2 were observed in HCCs compared with the corresponding noncancerous liver tissues. DNA hypermethylation on CpG islands of the p16 (8% and 66%) and hMLH1 (0% and 0%) genes and methylated in tumor (MINT) 1 (6% and 34%), 2 (24% and 58%), 12 (21% and 33%), 25 (0% and 5%), and 31 (0% and 23%) clones, and DNA hypomethylation on satellites 2 and 3 (18% and 67%), were detected in noncancerous liver tissues and HCCs, respectively. There was no significant correlation between the expression level of any DNA methyltransferase and DNA methylation status. Reduced expression of DNA repair protein, MBD4, was significantly correlated with poorer tumor differentiation and involvement of portal vein. Slightly reduced expression of MBD2 was detected in HCCs, and the expression of MeCP2 was particularly reduced in HCCs with portal vein involvement. These data suggest that overexpression of DNMT1 and DNMT3a, DNA hypermethylation on CpG islands, and DNA hypomethylation on pericentromeric satellite regions are early events during hepatocarcinogenesis, and that reduced expression of MBD4 may play a role in malignant progression of HCC.
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PMID:Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. 1123 Jul 35

DNA methylation modifies gene expression. Methylation patterns are established during ontogeny, but they change with aging, usually with a net decrease in methylation. The significance of this change in T cells is unknown, but it could contribute to autoimmunity, senescence, or both. We examined the effects of a null mutation in DNA methyltransferase 1 (Dnmt1), a gene maintaining DNA methylation patterns, on immune aging. Whereas aged control mice developed hypomethylated DNA, autoimmunity, and signs of immune senescence as predicted, the knockout mice surprisingly increased DNA methylation and developed signs of autoimmunity and senescence more slowly. To identify potential mechanisms, we compared transcripts of DNA methyltransferase and methylcytosine binding protein family members in control and knockout mice. MeCP2, a methylcytosine binding protein involved in gene suppression and chromatin inactivation, was the only transcript differentially expressed between old knockout mice and controls, and thus it is a candidate for a gene product mediating these effects.
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PMID:Unexpected effects of a heterozygous dnmt1 null mutation on age-dependent DNA hypomethylation and autoimmunity. 1138 89

DNA methylation, chromatin structure, transcription, and cancer have traditionally been studied as separate phenomena. Recent data provide now direct physical and functional links between these processes revealing a complex network of interactions and mutual dependences. Methylated DNA is bound by methyl-CpG binding protein (MeCP) complexes that include histone deacetylases (HDACs). This recruitment of HDACs is suggested to promote local chromatin condensation and thereby repress gene expression. Most recently, also complexes of DNA methyltransferase (Dnmt1) with transcriptional repressors, DMAP1 and pRB, have been described providing a direct link to transcriptional regulation and tumor suppression. Inactivation of the DNA methyltransferase genes (Dnmt1, 3a, and 3b) was found to be lethal in mice and several human diseases (ICF and Rett syndrome) turned out to be linked to DNA methylation. In particular, global hypomethylation has been found in tumor samples together with cancer-type-specific, local hypermethylation. Taken together, these lines of evidence clearly underscore the central role of DNA methylation in the regulation of gene expression and chromatin structure during normal development and diseases like cancer. J. Cell. Biochem. Suppl. 35:78-83, 2000.
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PMID:DNA methylation, nuclear structure, gene expression and cancer. 1138 35

During mammalian cell division, DNA methylation patterns are transferred accurately to the newly synthesized DNA strand. This depends on maintenance DNA methyltransferase activity. DNA methylation can affect chromatin organization and gene expression by recruitment of histone deacetylases (HDACs). Here we show that the methyl-CpG binding protein, MeCP2, interacts directly with the maintenance DNA methyltransferase, Dnmt1. The region of MeCP2 that interacts with Dnmt1 corresponds to the transcription repressor domain which can also recruit HDACs via a corepressor, mSin3A. Dnmt1 can form complexes with HDACs as well as MeCP2. Surprisingly, the MeCP2-Dnmt1 complex does not contain the histone deacetylase, HDAC1. Thus, Dnmt1 takes the place of the mSin3A-HDAC1 complex, indicating that the MeCP2-interacting Dnmt1 does not bind to HDAC1. Further, we demonstrate that MeCP2 can form a complex with hemimethylated as well as fully methylated DNA. Immunoprecipitated MeCP2 complexes show DNA methyltransferase activity to hemimethylated DNA. These results suggest that Dnmt1 associates with MeCP2 in order to perform maintenance methylation in vivo. We propose that genome-wide and/or -specific local DNA methylation may be maintained by the Dnmt1-MeCP2 complexes, bound to hemimethylated DNA. Dnmt1 may be recruited to targeted regions via multiple steps that may or may not involve histone deacetylases.
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PMID:Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1. 1247 78

The DNA methyltransferases, Dnmts, are the enzymes responsible for methylating DNA in mammals, which leads to gene silencing. Repression by DNA methylation is mediated partly by recruitment of the methyl-CpG-binding protein MeCP2. Recently, MeCP2 was shown to associate and facilitate histone methylation at Lys9 of H3, which is a key epigenetic modification involved in gene silencing. Here, we show that endogenous Dnmt3a associates primarily with histone H3-K9 methyltransferase activity as well as, to a lesser extent, with H3-K4 enzymatic activity. The association with enzymatic activity is mediated by the conserved PHD-like motif of Dnmt3a. The H3-K9 histone methyltransferase that binds Dnmt3a is likely the H3-K9 specific SUV39H1 enzyme since we find that it interacts both in vitro and in vivo with Dnmt3a, using its PHD-like motif. We find that SUV39H1 also binds to Dnmt1 and, consistent with these interactions, SUV39H1 can purify DNA methyltransferase activity from nuclear extracts. In addition, we show that HP1beta, a SUV39H1-interacting partner, binds directly to Dnmt1 and Dnmt3a and that native HP1beta associates with DNA methyltransferase activity. Our data show a direct connection between the enzymes responsible for DNA methylation and histone methylation. These results further substantiate the notion of a self-reinforcing repressive chromatin state through the interplay between these two global epigenetic modifications.
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PMID:The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. 1271 75


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