Regions of Focal DNA Hypermethylation and Long-Range Hypomethylation in Colorectal Cancer Coincide with Nuclear Lamina-Associated Domains
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32399 | GEO | 2011/09/27
SECONDARY ACCESSION(S): PRJNA147931
REPOSITORIES: GEO
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Project description:Osteosarcomas (OS) arise more commonly during the rapid bone growth and remodeling, thus it is plausible to infer the relationship between their tumorigenesis and cell cycle disruption by genetic and epigenetic factors. Methylation data of 28 primary OS was obtained using the HM450K microarray, and compared with nine normal bone tissues. The tumor mutational burden was analyzed using data from the TruSight One sequencing panel. We identified 3,146 differentially methylated positions, and OS presented high methylation heterogeneity, with global hypomethylation and focal hypermethylation at CpG islands. There were 319 hypomethylated and 266 hypermethylated regions in tumors, located in the promoter regions of 172 and 178 genes, respectively. These genes were enriched for biological processes related to skeletal system morphogenesis, proliferation, inflammatory response and signal transduction. Six tumor suppressors presented deletions or hypermethylation (DLEC1, GJB2, HIC1, MIR149, PAX6, WNT5A), and four oncogenes presented gains or hypomethylation (ASPSCR1, NOTCH4, PRDM16, RUNX3). Most cases did not report mutations in DNMTs or TETs, but DNMT3B was recurrently gained, a possible explanation for the hypermethylation at CpG islands. Our analysis also revealed hypomethylation at 6p22, a region that contains several genes, including histones. Overall, aberrant DNA methylation was spread throughout the genome of osteosarcomas, presented with high variance, similar to other molecular alterations. While the open-sea hypomethylation likely contributes to genomic instability, enriched CpG island hypermethylation suggests the involvement of mechanisms related to silencing tumor suppressor genes in osteosarcoma tumorigenesis. These data also suggest DNMT3B probably impacting biological processes associated with early bone development.
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Project description:Purpose: To establish pancreatic cancer-related aberrnat DNA methylation patterns, especially in CGI, CGI shore, orphan CGI and non-CGI promoter region and provide diagnosis or prognosis biomarker for pancreatic cancer dignosis or prognosis prediction Methods:MBD methylCap/seq was carried out to screen differentially methylated CpG islands in 3 libraries which includes 1 pancreatic cancer mix library, 1 adjacent normal tissue mix library and 1 normal pancreas tissue. MSP and multiplex-BSP validation was performed in independent tumor and adjacent tissues. Results: 66807 Hypermethylation DMR and 46815 Hypomethylation DMR were discovered in whole pancreatic cancer genome. 5280 Hypermethylation and 3488 Hypomethylation CpGI region were related gene promoter or gene body. Gene expression of 10 aberrant DMR were related with their methylation status validated by MSRE-qPCR and RT-PCR in 5-aza’ treated pancreatic cancer cell line. 40 DMR were validated in pancreatic cancer and adjacent tissues with MSP and gene ontology analysis showed seven of them were related with regulation of transcription(GO:0006355) which included DLX4,ELAVL2,IRX1,PITX2,SIM2,TBX5,TFAP2C. Conclusions: Methylcap-seq identified hundreds of DMR genes and regions which might involve with gene expression regulation and could be used as biological markers of pancreatic cancer therapy target or diagnosis.
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Project description:Lung cancer occurs in never-smokers. Epigenetic changes in lung cancer potentially represent important diagnostic, prognostic, and therapeutic targets. We compared DNA methylation profiles of 28 adenocarcinomas of the lungs of never-smokers with paired adjacent nonmalignant lung tissue. We correlated differential methylation changes with gene expression changes from the same 28 samples. We observed a distinct separation in methylation profiles between tumor and adjacent nonmalignant lung tissue using principal component analysis. Tumors were generally hypomethylated compared with adjacent nonmalignant tissue. Of 1,906 differentially methylated CpG sites between tumor and nonmalignant tissue, 1,198 were within classically defined CpG islands where tumors were hypermethylated compared with nonmalignant tissue. A total of 708 sites were outside CpG islands where tumors were hypomethylated compared with nonmalignant tissue. There were significant differences in expression of 351 genes (23%) of the 1,522 genes matched to the differentially methylated CpG sites. Genes that were not significantly differentially expressed and were hypermethylated within CpG sites were enriched for homeobox genes. These results suggest that the methylation profiles of lung adenocarcinomas of never-smokers and adjacent nonmalignant lung tissue are significantly different. Despite the differential methylation of homeobox genes, no significant changes in expression of these genes were detected. Twenty eight pairs of tumor and adjacent normal lungs were profiled for lung adenocarcinoma patients by gene expression and DNA methylation microarray
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Project description:CpG island promoter hypermethylation of tumor suppressor genes is a common hallmark of human cancer, and new large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells. Here we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKOcells). Using methylated DNA immunoprecipitation (MeDIP) methodology in conjunction with promoter microarray analyses we found that DKO cells experience a significant loss of hypermethylated CpG islands. Further characterization of these candidate sequences demonstrates CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine-nucleotide release factor RASGRF2, the apoptosis-associated basic helixloop transcription factor BHLHB9, and the homeobox gene HOXD1. Hypermethylation of these genes occurs already in premalignant lesions and accumulates during tumorigenesis. Thus, our results demonstrate the usefulness of DNMT genetic disruption strategies combined with MeDIP in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use. Keywords: Human Proximal Promoter Array; DNA Methylation Comparative experiment: methylated DNA immunoprecipitated/INPUT(Total Genomic DNA) from the colon cancer cell line HCT116 wild type vs methylated DNA imonoprecipitated/INPUT from the colon cancer cell line HCT116 DNMT1/3b doubleknockout (DKO)
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Project description:CpG island promoter hypermethylation of tumor suppressor genes is a common hallmark of human cancer, and new large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells. Here we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKOcells). Using methylated DNA immunoprecipitation (MeDIP) methodology in conjunction with promoter microarray analyses we found that DKO cells experience a significant loss of hypermethylated CpG islands. Further characterization of these candidate sequences demonstrates CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine-nucleotide release factor RASGRF2, the apoptosis-associated basic helixloop transcription factor BHLHB9, and the homeobox gene HOXD1. Hypermethylation of these genes occurs already in premalignant lesions and accumulates during tumorigenesis. Thus, our results demonstrate the usefulness of DNMT genetic disruption strategies combined with MeDIP in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use. Keywords: Human Proximal Promoter Array; DNA Methylation
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