We are analyzing https://link.springer.com/article/10.1007/s00401-011-0803-5.

Title:
A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts | Acta Neuropathologica
Description:
O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl DNA adducts such as those induced by alkylating agents. Loss of MGMT expression through transcriptional silencing by hypermethylation of its CpG island (CGI) is found in diverse human cancers including glioblastomas. Glioblastomas that have MGMT methylation respond to temozolomide, an alkylating agent, resulting in improved survival. Consequently, assessment of MGMT methylation has become a therapy response and prognostic indicator. However, it is not clear whether the region of the MGMT CGI commonly analysed is the critical region involved in transcriptional control. We measured methylation levels at each CpG site for the entire MGMT CGI using bisulfite modification and pyrosequencing, and compared them with MGMT mRNA expression in glioblastoma cell lines, xenografts and normal brain tissues (41 samples). Two critical regions were identified (DMR1 and DMR2). DMR2 encompasses the commonly analysed region and was always methylated when DMR1 was methylated. A luciferase reporter assay showed that substitutions of several specific CpG sites within DMR2 significantly attenuated the promoter activity of the MGMT CGI. Our results indicate that several CpG sites within DMR2 play a critical role in the transcriptional control of MGMT, making DMR2 the optimal target for methylation testing. However, given the highly variable patterns of MGMT methylation associated with transcriptional silencing observed in this region among the tumours in this study, methylation levels need to be measured at a number of individual CpGs within DMR2 to confidently predict transcriptional silencing and thus sensitivity to alkylating agents.
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Keywords {🔍}

article, google, scholar, pubmed, cas, mgmt, methylation, cpg, methyltransferase, dna, human, glioblastoma, promoter, gene, region, dmr, omethylguaninedna, analysis, nucleosome, cancer, supplementary, island, silencing, site, transcriptional, methylated, expression, cgi, pyrosequencing, cell, lines, sites, pcr, transcription, start, acta, collins, ichimura, temozolomide, access, omethylguanine, mol, privacy, cookies, content, critical, alkylating, regions, quantitative, glioma,

Topics {✒️}

o6-methylguanine-dna methyltransferase gene o6-methylguanine-dna methyltransferase status multiple test-corrected p-values o6-methylguanine dna methyltransferase o6-methylguanine-dna methyltransferase month download article/chapter newly diagnosed glioblastoma methylation-related chromatin structure dna-encoded nucleosome organization jp/research/db/tfsearch o6-methylguanine methyltransferase p14arf/mdm2/p53 pathway cpg methylation-dependent repression high-performance liquid chromatography recurrent high-grade glioma luciferase assay results full article pdf related subjects dna repair protein poor dna methylation privacy choices/manage cookies methylation-specific pcr mgmt methylation status primary human neoplasia mgmt cgi methylation human astrocytic gliomas glioblastoma cell lines temozolomide versus procarbazine transcription factors predicted mgmt methylation respond chromatin structure alteration methylation hot spots commonly analysed region entire mgmt cgi transcription start site normal brain tissues neoplastic brain components german glioma network koichi ichimura nucleosome occupancy prediction promoter cpg island dna repair dna methylation modulate mgmt activity european economic area check access adenovirus-mediated overexpression induces replicative senescence exon/intron boundary eortc-ncic trial

Questions {❓}

Segal E, Widom J (2009) What controls nucleosome positions?

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         headline:A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts
         description:O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl DNA adducts such as those induced by alkylating agents. Loss of MGMT expression through transcriptional silencing by hypermethylation of its CpG island (CGI) is found in diverse human cancers including glioblastomas. Glioblastomas that have MGMT methylation respond to temozolomide, an alkylating agent, resulting in improved survival. Consequently, assessment of MGMT methylation has become a therapy response and prognostic indicator. However, it is not clear whether the region of the MGMT CGI commonly analysed is the critical region involved in transcriptional control. We measured methylation levels at each CpG site for the entire MGMT CGI using bisulfite modification and pyrosequencing, and compared them with MGMT mRNA expression in glioblastoma cell lines, xenografts and normal brain tissues (41 samples). Two critical regions were identified (DMR1 and DMR2). DMR2 encompasses the commonly analysed region and was always methylated when DMR1 was methylated. A luciferase reporter assay showed that substitutions of several specific CpG sites within DMR2 significantly attenuated the promoter activity of the MGMT CGI. Our results indicate that several CpG sites within DMR2 play a critical role in the transcriptional control of MGMT, making DMR2 the optimal target for methylation testing. However, given the highly variable patterns of MGMT methylation associated with transcriptional silencing observed in this region among the tumours in this study, methylation levels need to be measured at a number of individual CpGs within DMR2 to confidently predict transcriptional silencing and thus sensitivity to alkylating agents.
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      description:O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl DNA adducts such as those induced by alkylating agents. Loss of MGMT expression through transcriptional silencing by hypermethylation of its CpG island (CGI) is found in diverse human cancers including glioblastomas. Glioblastomas that have MGMT methylation respond to temozolomide, an alkylating agent, resulting in improved survival. Consequently, assessment of MGMT methylation has become a therapy response and prognostic indicator. However, it is not clear whether the region of the MGMT CGI commonly analysed is the critical region involved in transcriptional control. We measured methylation levels at each CpG site for the entire MGMT CGI using bisulfite modification and pyrosequencing, and compared them with MGMT mRNA expression in glioblastoma cell lines, xenografts and normal brain tissues (41 samples). Two critical regions were identified (DMR1 and DMR2). DMR2 encompasses the commonly analysed region and was always methylated when DMR1 was methylated. A luciferase reporter assay showed that substitutions of several specific CpG sites within DMR2 significantly attenuated the promoter activity of the MGMT CGI. Our results indicate that several CpG sites within DMR2 play a critical role in the transcriptional control of MGMT, making DMR2 the optimal target for methylation testing. However, given the highly variable patterns of MGMT methylation associated with transcriptional silencing observed in this region among the tumours in this study, methylation levels need to be measured at a number of individual CpGs within DMR2 to confidently predict transcriptional silencing and thus sensitivity to alkylating agents.
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