Unknown,Transcriptomics,Genomics,Proteomics

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Global DNA methylation landscape reveals roles of DNA methylation involved in the regulation of drug metabolizing enzyme [III]

ABSTRACT: In order to elucidate the role of DNA methylation in the DME gene regulation, global DNA methylation and mRNA expression profiles of human tissues and cell lines were examinde by HumanMethylation450 Bead Chip and SurePrint G3 Human Gene Expression 8×60K v2. We demonstrated DNA methylation landscape of the DME genes in human tissues. Although a fraction of DME genes can be regulated by their DNA methylation, the variable DNA methylation status probably affects drug metabolism and response. Bisulphite converted DNA from the 4 samples were hybridized to the Illumina HumanMethylation450 BeadChip (Sample L and SI were examined twice).

ORGANISM(S): Homo sapiens

SUBMITTER: Wataru Habano

PROVIDER: E-GEOD-67484 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intrauterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. In a unique cohort of 17 monozygotic (MZ) monochorionic female twins very discordant for birth weight (relative differences ranging from 21.3-35.7%), we examined if adverse prenatal growth conditions experienced by the smaller co-twins lead to systemic long-lasting DNA methylation changes. Genome-wide DNA methylation profiles were acquired from saliva DNA using the Infinium HumanMethylation450 BeadChip, targeting ~2% of all CpGs in the genome. Results: Overall, co-twins showed very similar genome-wide DNA methylation profiles. Since observed differences were almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3153 were differentially methylated between the heavy and light co-twins at nominal significance (p<0.01), of which 45 showed absolute mean β-value differences >0.05 (max=0.08). Deep bisulfite sequencing of eight such loci revealed that differences remained in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicated no significant intra-pair differences. Conclusions: Severe intrauterine growth differences observed within these MZ twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies. DNA methylation profiles of saliva from 17 Adult Female MZ MC Twins discordant for birth weight.

Project description:Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. The initial lesion is believed to be the relatively benign precursor lesion (ICGNU), from which either highly chemosensitive seminomas or the more aggressive non-seminomas develop. Previous analyses of selected genes have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. However, the genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumoursâ biology have not yet been established. Here genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data. This demonstrated that the seminoma cells exhibited very little aberrant DNA methylation while non-seminoma cells exhibited very high levels of DNA methylation. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested did indeed play a role in their silencing and many of these genes were also differentially expressed in primary tumours. Through this approach the genes silenced in the various GCT cell lines were identified. Conclusions: Several pluripotency-associated genes, never before implicated in this type of cancer, were identified as a major functional group of silenced genes. Silencing of these factors that normally suppress somatic differentiation might play an important role in the progression to non-seminoma formation. Genomic DNA and RNA was extracted from cell lines representing four subtypes of GCT. RNA was subjected to Affymetric expression array analysis while DNA was bisulfite treated and analysed using Illumina Infinium 450K arrays. Statistical approaches were used to correlate methylation and expression for each gene.

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Global DNA methylation landscape reveals roles of DNA methylation involved in the regulation of drug metabolizing enzyme [III]

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