X-chromosome inactivation and cell memory

Riggs, Arthur D.

doi:10.1016/0168-9525(92)90090-q

Cited by 124 publications

(114 citation statements)

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“…26 A threshold was defined for each gene and each tissue, leading to significant differences in the methylation frequencies of the genes examined, even though promoter methylation in normal, non-neoplastic tissues has been demonstrated previously. [13][14][15]17,28,29 Therefore, taking NLT for threshold calculation in real-time MSP may lead to false negative results for promoter methylation. 26,30 In our study, lower APC methylation in CT compared to HCC and NLT (97.5 in HCC vs. 6.6 in CT, both p < 0.001) could be explained by the relative lower amount of hepatocytes compared to connective tissue in cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver

Harder

Opitz

Brabender

et al. 2008

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Little is known about its molecular pathogenesis and the relevance of DNA methylation for disease initiation and progression. Nevertheless, promoter methylation of some genes has been implicated as potential marker for HCC. Thirty-four HCC, 34 matching non-malignant, cirrhotic livers and 16 normal livers were analyzed for the methylation status of the genes p16 INK4a , GSTP1, MGMT, DAP-K and APC by quantitative methylation-specific PCR. DNA promoter methylation frequencies in HCC and matching non-malignant cirrhotic liver, respectively, were as follows: p16 INK4a (76% vs. 24%), GSTP1 (53% vs. 32%), MGMT (6 vs. 12%), DAP-K (68 vs. 100%) and APC (100 vs. 100%). GSTP1 and/or p16 INK4a promoter methylation was observed in 88% of the HCC samples. In normal liver tissue, the p16 INK4a , GSTP1 and MGMT promoter were not methylated. DAP-K was methylated in 31% and APC even in 100% of normal liver samples. Quantitative levels of methylated promoter DNA of all genes were significantly different in the various tissue types except for MGMT. Our results suggest that promoter methylation of tumor-associated genes is a common event in hepatocarcinogenesis. Significantly, higher levels and frequencies of promoter methylation in HCC were found for p16 INK4a and GSTP1 compared to non-malignant cirrhotic liver. This indicates that these epigenetic events may serve as a good marker for HCC. These data also demonstrate the importance of the quantification of methylated promoter DNA within a given sample and the use of normal tissue as controls. Quantitative analyses of methylated GSTP1 and p16 INK4a promoter may serve as a powerful molecular marker in detecting HCC in biopsies.

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Section: Discussionmentioning

confidence: 99%

Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver

Harder

Opitz

Brabender

et al. 2008

Intl Journal of Cancer

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“…normal development of animals 10,11 and plants [12][13][14] via effects on gene repression 15 , Xchromosome inactivation 16 , genomic imprinting 17 and replication timing 18 .…”

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confidence: 99%

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

et al. 2002

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The PWWP domain is a weakly conserved sequence motif found in >60 eukaryotic proteins, including the mammalian DNA methyltransferases Dnmt3a and Dnmt3b. These proteins often contain other chromatin-association domains. A 135-residue PWWP domain from mouse Dnmt3b (amino acids 223-357) has been structurally characterized at 1.8 Å resolution. The N-terminal half of this domain resembles a barrel-like five-stranded structure, whereas the C-terminal half contains a five-helix bundle. The two halves are packed against each other to form a single structural module that exhibits a prominent positive electrostatic potential. The PWWP domain alone binds DNA in vitro, probably through its basic surface. We also show that recombinant Dnmt3b2 protein (a splice variant of Dnmt3b) and two N-terminal deletion mutants (Δ218 and Δ369) have approximately equal methyl transfer activity on unmethylated and hemimethylated CpG-containing oligonucleotides. The Δ218 protein, which includes the PWWP domain, binds DNA more strongly than Δ369, which lacks the PWWP domain.Genomic patterns of cytosine methylation at the C5 position play key roles in the organization and control of mammalian chromatin (reviewed in refs 1-3). Mammalian DNA methyltransferases (MTases) all contain a C-terminal catalytic region that is structurally and functionally homologous to bacterial MTases. The eukaryotic DNA MTases have been grouped into three families based on (i) distinctive properties of their N-terminal regions and (ii) intriguing differences in DNA substrate preferences. The first eukaryotic DNA MTase, Dnmt1, contains a large N-terminal regulatory region of ~1,000 amino acids and shows a preference for hemimethylated DNA in vitro [4][5][6] . Dnmt2, a relatively small protein, contains only the MTase domain, and its function is still unclear 7 . Recombinant Dnmt3 acts on unmethylated and hemimethylated DNA at equal rates in vitro 8,9 .The task of dissecting the functional roles of the N-terminal region of the different MTase families is just beginning. These regions vary widely in size and are probably responsible for the diverse biological functions of eukaryotic DNA MTases. These functions include the © 2002 Nature Publishing Group Correspondence should be addressed to X.C. xcheng@emory.edu. Competing interests statementThe authors declare that they have no competing financial interests. HHS Public Access Dnmt3 contains a PWWP domainThe sequences of Dnmt3 orthologs have been determined from human and mouse. They all contain an N-terminal variable region (~280 amino acids in Dnmt3a and ~220 amino acids in Dnmt3b), followed by three stretches of conserved regions: the PWWP motif, six repeats of a CXXC motif and a set of 10 motifs conserved among DNA MTase catalytic regions (Fig. 1a). The PWWP motif 28 was first identified in a gene family related to the hepatomaderived growth factor (HDGF) 29 and WHSC1 genes (Wolf-Hirschhorn Syndrome Candidate) 30 . The corresponding sequence in Dnmt3 is SWWP (Fig. 1b); only the last two positions of the motif...

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“…CpG islands are usually unmethylated in normal tissues, except in the case of imprinted genes, X chromosome in women, germline-or tissuespecific genes. [3][4][5][6] Promoter hypermethylation causes a transcriptional block in the genes involved. Indeed, silencing of functionally relevant genes via aberrant DNA methylation has been linked to diverse human pathologies.…”

Section: Introductionmentioning

confidence: 99%

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

et al. 2003

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Multiple genes have been shown to be independently hypermethylated in lymphoid malignancies. We report here on the extent of concurrent methylation of E-cadherin, Dap-kinase, O 6 MGMT, p73, p16, p15 and p14 in 129 pediatric ALL cases. While most of these genes demonstrated methylation in a proportion of cases, O 6 MGMT, p16 and p14 were infrequently methylated (11, 7 and 3%, respectively). Methylation of at least one gene was found in the vast majority (83%) of cases. To determine the extent and concordance of methylation we calculated a methylation index (MI ¼ number of methylated genes/number of studied genes) for each sample. The average MI was 0.28, corresponding to 2/7 methylated genes. MI was correlated with standard prognostic factors, including immunophenotype, age, sex, WBC and presence of specific translocations (TEL-AML1, BCR-ABL, E2A-PBX1 or MLL-AF4). We determined that children X10 years old and children presenting with high WBC (X50 Â 10 9 /l) both associated with a higher MI (Po0.01 and o0.05, respectively). T-ALLs demonstrated a lower MI (median ¼ 0.17) than precursor B ALLs (median ¼ 0.28). Among the different molecular subgroups, MLL-ALLs had the highest MI (mean ¼ 0.35), while ALLs carrying the t(1;19) had the lowest MI (mean ¼ 0.07). The most common epigenetic lesion in childhood ALL was methylation of E-cadherin (72%) independent of the molecular subtype or other clinicopathological factors.

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X-chromosome inactivation and cell memory

Cited by 124 publications

References 0 publications

Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver

Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

Concurrent methylation of multiple genes in childhood ALL: Correlation with phenotype and molecular subgroup

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