Methylome of a low-grade invasive GIST
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Henri-Jacques Delecluse
PROVIDER: E-GEOD-55521 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2011-01-19 | E-GEOD-22867 | biostudies-arrayexpress
Project description:The DNA methylation patterns associated with the development and progression of cancer. The aim of the present study was to identify novel methylation markers that can discriminate between normal and Non-muscle-invasive bladder cancer (NMIBC), and between good and poor prognosis using microarray analysis of DNA methylation and RNA expression patterns in NMIBC patients. From the 24 matched microarray-based DNA methylation and gene expression profiling data set, tumor specific hypermethylated genes were selected and clinical relevance of these genes were verified by quantitative PQS analyses. Methylation statues of several genes were significantly associated with decreased gene expression levels and aggressive clinicopathological characteristics. In multivariate regression analyses, hypermethylation of these genes were the independent predictors of recurrence and progression. Genomic DNA was extracted by standard methods using the Wizard Genomic DNA Purification System (Promega, Madison, WI). Total RNA was extracted with TRIzol reagent (Life Technologies, NY) according to the manufacturer’s protocol. Methylation patterns were assayed using the genome-wide Illumina Infinium HumanMethylation27 BeadChip array (Illumina Inc., San Diego, CA). Methylation assays were carried out according to the manufacturer’s protocol. Bisulfite conversion of genomic DNA was performed using the EZ DNA Methylation Kit (Zymo Research, Orange, CA). Fluorescence signals corresponding to C or T nucleotides were measured and the data were used to assign a quantitative measure of methylation level (β value). The β value is a quantitative measure of DNA methylation levels of specific CpGs and ranges from 0 for completely unmethylated to 1 for completely methylated.
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Project description:Methylation of DNA at CpG dinucleotides represents one of the most important epigenetic mechanisms involved in the control of gene expression in vertebrate cells. In this report, we conducted high-throughput nucleosome reconstitution experiments on 572 KB of human DNA and 668 KB of mouse DNA that was unmethylated or methylated in order to investigate the effects of this epigenetic modification on the positioning and stability of nucleosomes. The DNA loci from both species contained the genes that encode the serum albumin family, the MYC protein, and the tumor suppressor p53. The results demonstrated that a small subset of nucleosomes positioned by nucleotide sequence was sensitive to methylation where the modification increased the affinity of these sequences for the histone octamer. The features that distinguished these nucleosomes from the bulk of the methylation-insensitive nucleosomes were an increase in the frequency of CpG dinucleotides and a unique rotational orientation of CpGs such that their minor grooves tended to face toward the histones in the nucleosome rather than away. We propose that these features serve to enhance the affinity of methylated DNA for the histone octamer and that this effect could be involved in gene regulatory mechanisms such as silencing. These methylation-sensitive nucleosomes were preferentially associated with exons as compared to introns while unmethylated CpG islands near transcription start sites became enriched in nucleosomes upon methylation. The results of this study suggest that the effects of DNA methylation on nucleosome stability in vitro can recapitulate what has been observed in the cell and provide a direct link between DNA methylation and the structure and function of chromatin. For the human data, there were 3 unmethylated nucleosome replicates, 2 methylated nucleosome replicates, an unmethylated MNase control, and an unmethylated sonicated control. For the mouse data, there were 2 unmethylated nucleosome replicates, 2 methylated nucleosome replicates, an unmethylated MNase control, a methylated MNase control, and an unmethylated sonicated control.
2013-01-28 | E-GEOD-37224 | biostudies-arrayexpress
Project description:We applied the solution hybrid selection approach to the enrichment of CpG islands (CGIs) and promoter sequences from the human genome for targeted high-throughput bisulfite sequencing. A single lane of Illumina sequences allowed accurate and quantitative analysis of 1 million CpGs in more than 21,408 CGIs and 15,946 transcriptional regulatory regions. More than 85% of capture probes successfully yielded quantitative DNA methylation information of targeted regions. In this study, we generated genome-wide, single-base resolution DNA methylation maps in three of the most commonly used breast cancer cell lines.Differentially methylated regions (DMRs) were identified in the 5?-end regulatory regions, as well as the intra- and intergenic regions, particularly in the X chromosome among the three cell lines. The single CpG resolution methylation maps of many known tumor suppressor genes were also established in the three cell lines. Here we present a novel approach that combines solution-phase hybrid selection and massively parallel bisulfite sequencing to profile DNA methylation in targeted CGI and promoter regions. We designed 51,466 single strand DNA oligonucleotides (160-mer) which target 23,441 CGIs and the transcription start sites of 19,369 known genes in the human genome. The synthetic long DNA oligonucleotides were converted into biotinylated RNA probes for solution-phase hybridization capture of target DNA. The captured genomic DNA was treated with sodium bisulfite, amplified by PCR and sequenced using Illumina GA IIx sequencer.
2011-08-01 | E-GEOD-26826 | biostudies-arrayexpress
Project description:We conducted a genome-wide DNA methylation analysis in CD19+ B-cells from CLL patient and normal control samples using reduced representation bisulfite sequencing (RRBS). The methylation status of 1.8-2.3 million CpGs in the CLL genome was determined; about 45% of these CpGs were located in more than 23,000 CpG islands (CGIs). While global CpG methylation was similar between CLL and normal B-cells, 1764 gene promoters were identified as being differentially methylated between the two groups. Aberrant hypermethylation was found in all HOX gene clusters and a significant number of WNT signaling pathway genes. The genes that were frequently hypermethylated were typically associated with histone H3 lysine 27 tri-methylation or bivalent domains in normal B-cells. An additional 152 genes were found to be differentially methylated between normal naïve and memory B-cells. Of these 152 genes, 123 were hypomethylated in memory B-cells when compared to naïve B-cells. Overall, CLL B-cells had methylation patterns more similar to memory B-cells than naïve B-cells. Cluster analysis showed that the tissue-specific methylated genes separated CLL samples into two groups with differential ZAP70 methylation status. Hypomethylation occurred more frequently in the gene body including introns, exons, and 3'-UTRs in CLL. The hypomethylation in the NFATc1 P2 promoter and first intron correlated with up-regulation of both NFATc1 RNA and protein expression levels in CLL suggesting that an epigenetic mechanism is involved in the constitutive activation of NFAT activity in CLL cells. This comprehensive DNA methylation map will further our understanding of the epigenetic contribution to cellular dysfunction in CLL. To perform a genome-wide analysis of DNA methylation in CLL, we applied the Reduced Representation Bisulfite Sequencing (RRBS) to CD19+ B-cells isolated from normal control and CLL peripheral blood samples. The genomic DNA from each sample was digested with the methylation-insensitive restriction enzyme MspI (restriction site, CCGG) and ligated to Illumina sequencing adaptors containing methylated cytosine residues. The ligated MspI fragments were size-selected, treated with sodium bisulfite, and amplified by PCR. The PCR products were purified and sequenced using Illumina GAIIx sequencer with a read length of 52 or 76bp. 11 CLL B-cell samples, 3 normal control samples including one each of normal CD19+, CD19+/ IgD+ naïve, and CD19+/CD27+ memory B-cell sample and three CLL cell lines (Mec-1, Mec-2, and Wac-3) were used. We generated 20-30 million Illumina sequencing reads for each sample.
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