Global hypomethylation identifies loci targeted for hypermethylation in head and neck cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE25093 | GEO | 2011/10/28
SECONDARY ACCESSION(S): PRJNA134763
REPOSITORIES: GEO
Similar Datasets
Project description:The human epigenome is profoundly altered in cancers, with a characteristic loss of methylation in repetitive regions and concomitant accumulation of gene promoter methylation. The degree to which these processes are coordinated is unclear so we investigated both in head and neck squamous cell carcinomas.Global methylation was measured using the luminometric methylation assay (LUMA) and pyrosequencing of LINE-1Hs and AluYb8 repetitive elements in a series of 138 tumors. We also measured methylation of more than 27,000 CpG loci with the Illumina HumanMethylation27 Microarray (n = 91).LINE-1 methylation was significantly associated with LUMA and Infinium loci methylation (Spearman's ? = 0.52/? = 0.56, both P < 0.001) but not that of AluYb8. Methylation of LINE-1, AluYb8, and Infinium loci differed by tumor site (each Kruskal-Wallis, P < 0.05). Also, LINE-1 and LUMA methylation were associated with HPV16 E6 serology (each Mann-Whitney, P < 0.05). Comparing LINE-1 methylation to gene-associated methylation, we identified a distinct subset of CpG loci with significant hypermethylation associated with LINE-1 hypomethylation. An investigation of sequence features for these CpG loci revealed that they were significantly less likely to reside in repetitive elements (Gene Set Enrichment Analysis, P < 0.02), enriched in CpG islands (P < 0.001) and were proximal to transcription factor-binding sites (P < 0.05). We validated the top CpG loci that had significant hypermethylation associated with LINE-1 hypomethylation (at EVI2A, IFRD1, KLHL6, and PTPRCAP) by pyrosequencing independent tumors.These data indicate that global hypomethylation and gene-specific methylation processes are associated in a sequence-dependent manner, and that clinical characteristics and exposures leading to HNSCC may be influencing these processes.
| S-EPMC3107873 | biostudies-literature
Project description:Genome-wide DNA methylation profiling of head and neck squamous cell carcinomas (HNSCCs). The Illumina Infinium 27k Human DNA methylation BeadChip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in fresh-frozen tumor tissues. Samples included 91 tumors from the oralpharynx and larynx, reflecting all stages of disease, 18 normal head and neck National Disease Research Interchange (NDRI) samples, and 213 normal control blood samples.
2011-10-28 | GSE25089 | GEO
Project description:Genome-wide DNA methylation profiling of head and neck squamous cell carcinomas. The Illumina Infinium 27k Human DNA methylation BeadChip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in fresh-frozen tumor tissues. Samples included 91 tumors from the oralpharynx and larynx, reflecting all stages of disease, 18 normal head and neck National Disease Research Interchange (NDRI) samples, and 213 normal control blood samples.
2011-10-28 | GSE25083 | GEO
Project description:Genome-wide DNA methylation profiling of head and neck squamous cell carcinomas (HNSCCs). The Illumina Infinium 27k Human DNA methylation BeadChip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in fresh-frozen tumor tissues. Samples included 91 tumors from the oralpharynx and larynx, reflecting all stages of disease, 18 normal head and neck National Disease Research Interchange (NDRI) samples, and 213 normal control blood samples.
2011-10-28 | GSE25091 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE25083: Global hypomethylation identifies loci targeted for hypermethylation in head and neck cancer: normal head and neck tissue GSE25089: Global hypomethylation identifies loci targeted for hypermethylation in head and neck cancer: HNSCC GSE25091: Global hypomethylation identifies loci targeted for hypermethylation in head and neck cancer: blood controls Refer to individual Series
2011-10-27 | E-GEOD-25093 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of head and neck squamous cell carcinomas (HNSCCs). The Illumina Infinium 27k Human DNA methylation BeadChip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in fresh-frozen tumor tissues. Samples included 91 tumors from the oralpharynx and larynx, reflecting all stages of disease, 18 normal head and neck National Disease Research Interchange (NDRI) samples, and 213 normal control blood samples. Bisulphite-converted DNA from the 91 head and neck squamous cell carcinoma samples were hybridized to the Illumina Infinium 27k Human Methylation Beadchip v1.2.
2011-10-27 | E-GEOD-25089 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of head and neck squamous cell carcinomas. The Illumina Infinium 27k Human DNA methylation BeadChip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in fresh-frozen tumor tissues. Samples included 91 tumors from the oralpharynx and larynx, reflecting all stages of disease, 18 normal head and neck National Disease Research Interchange (NDRI) samples, and 213 normal control blood samples. Bisulphite-converted DNA from the 18 normal head and neck samples were hybridized to the Illumina Infinium 27k Human Methylation Beadchip v1.2.
2011-10-27 | E-GEOD-25083 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of head and neck squamous cell carcinomas (HNSCCs). The Illumina Infinium 27k Human DNA methylation BeadChip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in fresh-frozen tumor tissues. Samples included 91 tumors from the oralpharynx and larynx, reflecting all stages of disease, 18 normal head and neck National Disease Research Interchange (NDRI) samples, and 213 normal control blood samples. Bisulphite-converted DNA from the 213 control blood samples were hybridized to the Illumina Infinium 27k Human Methylation Beadchip v1.2.
2011-10-27 | E-GEOD-25091 | biostudies-arrayexpress
Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ΔRFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-ΔRFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer.
2014-09-30 | GSE57829 | GEO
Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, the molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in a gain of DNMT1 function. However, a substantial body of data suggested that RFTS is required for DNMT1 activity. Here, we demonstrate that deletion of RFTS alters DNMT1-dependent DNA methylation during malignant transformation. Compared to full-length DNMT1, ectopic expression of hyperactive DNMT1-?RFTS caused greater malignant transformation and enhanced promoter methylation with condensed chromatin structure that silenced DAPK and DUOX1 expression. Simultaneously, deletion of RFTS impaired DNMT1 chromatin association with pericentromeric Satellite 2 (SAT2) repeat sequences and produced DNA demethylation at SAT2 repeats and globally. To our knowledge, RFTS-deleted DNMT1 is the first single factor that can reprogram focal hypermethylation and global hypomethylation in parallel during malignant transformation. Our evidence suggests that the RFTS domain of DNMT1 is a target responsible for epigenetic changes in cancer.
| S-EPMC4615144 | biostudies-literature