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DNMT1 and DNMT3b cooperate to silence genes in human cancer cells 总被引:81,自引:0,他引:81
Rhee I Bachman KE Park BH Jair KW Yen RW Schuebel KE Cui H Feinberg AP Lengauer C Kinzler KW Baylin SB Vogelstein B 《Nature》2002,416(6880):552-556
Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation. 相似文献
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Barreto G Schäfer A Marhold J Stach D Swaminathan SK Handa V Döderlein G Maltry N Wu W Lyko F Niehrs C 《Nature》2007,445(7128):671-675
DNA methylation is an epigenetic modification that is essential for gene silencing and genome stability in many organisms. Although methyltransferases that promote DNA methylation are well characterized, the molecular mechanism underlying active DNA demethylation is poorly understood and controversial. Here we show that Gadd45a (growth arrest and DNA-damage-inducible protein 45 alpha), a nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth, has a key role in active DNA demethylation. Gadd45a overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. Gadd45a knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 in Xenopus laevis oocytes, Gadd45a is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair and Gadd45a interacts with and requires the DNA repair endonuclease XPG. We conclude that Gadd45a relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks. 相似文献
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The conversion of a normal cell to a cancer cell occurs in several steps and typically involves the activation of oncogenes and the inactivation of tumour suppressor and pro-apoptotic genes. In many instances, inactivation of genes critical for cancer development occurs by epigenetic silencing, often involving hypermethylation of CpG-rich promoter regions. It remains to be determined whether silencing occurs by random acquisition of epigenetic marks that confer a selective growth advantage or through a specific pathway initiated by an oncogene. Here we perform a genome-wide RNA interference (RNAi) screen in K-ras-transformed NIH 3T3 cells and identify 28 genes required for Ras-mediated epigenetic silencing of the pro-apoptotic Fas gene. At least nine of these RESEs (Ras epigenetic silencing effectors), including the DNA methyltransferase DNMT1, are directly associated with specific regions of the Fas promoter in K-ras-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs results in failure to recruit DNMT1 to the Fas promoter, loss of Fas promoter hypermethylation, and derepression of Fas expression. Analysis of five other epigenetically repressed genes indicates that Ras directs the silencing of multiple unrelated genes through a largely common pathway. Last, we show that nine RESEs are required for anchorage-independent growth and tumorigenicity of K-ras-transformed NIH 3T3 cells; these nine genes have not previously been implicated in transformation by Ras. Our results show that Ras-mediated epigenetic silencing occurs through a specific, complex, pathway involving components that are required for maintenance of a fully transformed phenotype. 相似文献
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IDH mutation impairs histone demethylation and results in a block to cell differentiation 总被引:1,自引:0,他引:1
Lu C Ward PS Kapoor GS Rohle D Turcan S Abdel-Wahab O Edwards CR Khanin R Figueroa ME Melnick A Wellen KE O'Rourke DM Berger SL Chan TA Levine RL Mellinghoff IK Thompson CB 《Nature》2012,483(7390):474-478
Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells. 相似文献
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应用甲基化敏感扩增多态性(MSAP)技术检测小麦抗白粉病代换系6A/6V与感病品系京411的近等基因系NILs,及其亲本6A/6V和京411的基因组DNA甲基化变化.结果表明,NILs的整体甲基化水平(22.9%)略高于6A/6V(21.2%),低于京411(23.4%).分析其甲基化模式发现,NILs相对京411甲基化水平降低条带比例(2.89%)明显高于甲基化提高条带(0.55%),而相对抗病亲本6A/6V,NILs甲基化水平降低条带比例(2.96%)明显低于甲基化提高条带(4.20%),说明NILs的整体基因表达水平低于6A/6V,高于京411. 相似文献
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DNA甲基化在肿瘤形成中的作用(综述) 总被引:2,自引:0,他引:2
DNA甲基化改变是肿瘤细胞中常见的现象,DNA甲基化与肿瘤的发生有密切关系。从以下几方面对此做一综述。(1)简介哺乳动物细胞的DNA甲基化;(2)DNA甲基化与肿瘤基因突变;(3)肿瘤DNA甲基化的基因外作用,其中包括:原癌基因的低甲基化和抑癌基因的高甲基化。 相似文献
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LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription 总被引:4,自引:0,他引:4
Metzger E Wissmann M Yin N Müller JM Schneider R Peters AH Günther T Buettner R Schüle R 《Nature》2005,437(7057):436-439
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Cyclical DNA methylation of a transcriptionally active promoter 总被引:3,自引:0,他引:3
Métivier R Gallais R Tiffoche C Le Péron C Jurkowska RZ Carmouche RP Ibberson D Barath P Demay F Reid G Benes V Jeltsch A Gannon F Salbert G 《Nature》2008,452(7183):45-50
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Ferres-Marco D Gutierrez-Garcia I Vallejo DM Bolivar J Gutierrez-Aviño FJ Dominguez M 《Nature》2006,439(7075):430-436
Cancer is both a genetic and an epigenetic disease. Inactivation of tumour-suppressor genes by epigenetic changes is frequently observed in human cancers, particularly as a result of the modifications of histones and DNA methylation. It is therefore important to understand how these damaging changes might come about. By studying tumorigenesis in the Drosophila eye, here we identify two Polycomb group epigenetic silencers, Pipsqueak and Lola, that participate in this process. When coupled with overexpression of Delta, deregulation of the expression of Pipsqueak and Lola induces the formation of metastatic tumours. This phenotype depends on the histone-modifying enzymes Rpd3 (a histone deacetylase), Su(var)3-9 and E(z), as well as on the chromodomain protein Polycomb. Expression of the gene Retinoblastoma-family protein (Rbf) is downregulated in these tumours and, indeed, this downregulation is associated with DNA hypermethylation. Together, these results establish a mechanism that links the Notch-Delta pathway, epigenetic silencing pathways and cell-cycle control in the process of tumorigenesis. 相似文献
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Transient cyclical methylation of promoter DNA 总被引:3,自引:0,他引:3
Kangaspeska S Stride B Métivier R Polycarpou-Schwarz M Ibberson D Carmouche RP Benes V Gannon F Reid G 《Nature》2008,452(7183):112-115
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Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning 总被引:10,自引:0,他引:10
Cokus SJ Feng S Zhang X Chen Z Merriman B Haudenschild CD Pradhan S Nelson SF Pellegrini M Jacobsen SE 《Nature》2008,452(7184):215-219