Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early stage lung adenocarcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85301 | GEO | 2017/06/10
SECONDARY ACCESSION(S): PRJNA338134
REPOSITORIES: GEO
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Project description:Genome-wide methylation analysis was performed by methylated DNA immunoprecipitation (MeDIP)-CpG island (CGI) microarray analysis to identify candidate CGIs specifically methylated in mouse colon tumors associated with colitis. We sucessfully identified 23 candidate CGIs methylated in tumors.
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Project description:Genome-wide methylation analysis was performed by methylated DNA immunoprecipitation (MeDIP)-CpG island (CGI) microarray analysis to identify candidate CGIs specifically methylated in mouse colon tumors associated with colitis. We sucessfully identified 23 candidate CGIs methylated in tumors. Two samples were analyzed by MeDIP-CGI microarray. One is a pool of two AOM/DSS-induced colon tumors in BALB/c mice and another is a pool of two normal colonic epithelial cell samples obtained from untreated BALB/c mice by the crypt isolation technique. The pool of normal colonic epithelial cell samples was used as reference. Dye-swaps were not perfromed. The methylation statuses of CGIs identified by microarray were confirmed by another method, methylation-specific PCR.
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Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. Digital restriction enzyme analysis of methylation (DREAM) was performed to determine the DNA methylation profiles of HEK293T cells overexpressing mTET1-CD, TET1-CD, mTET1-FL, or TET1-FL. In this approach, genomic DNA is sequentially cut at CCCGGG sites with the methylation sensitive enzyme SmaI (blunt ends) and its methylation-tolerant neoschizomer XmaI (5M-bM-^@M-^YCCGG overhangs), creating different end sequences that represent methylation status of the CCCGGG sites. These end sequences are analyzed by next generation sequencing, and thereafter the methylation status at individual CCCGGG sites across the genome can be determined.
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Project description:Abnormal epigenetic gene regulation may play a pivotal role in atherogenesis. In particular, global DNA hypomethylation potentially leading to proatherogenic gene expression, occurs in atherosclerotic lesions in humans and animal models. In order to identify genomic sequences targeted for DNA hypomethylation in atherosclerosis, we analysed the methylation status of CpG islands (CGIs) in 45 human arteries with advanced atherosclerotic lesions and 16 normal counterparts by a microarray approach. Methylation data for 10,367 CGIs revealed that a subset (1.5%) of such sequences was hypermethylated in normal arteries, in accordance with data previously obtained in peripheral blood cells. Ninety-four per cent of this CGI subset was demethylated in atherosclerotic tissue, while only 17 of normally hypomethylated CGIs was hypermethylated in diseased tissue. A functional classification of genes physically associated with differentially methylated CGIs revealed a bias towards transcription factors (42%). The latter include HOX members, NOTCH1 and FOXP1, which are known to regulate angiogenesis, dedifferentiation, cell migration and macrophage function. The methylation status of selected CGIs was validated in further 10 subjects for either group. Expression patterns of these factors were compatible with the observed differential methylation. Our data suggest that one of the molecular changes associated with aberrant DNA methylation in advanced atherosclerosis is the regulation of critical transcription factor genes for the induction of a proatherogenic cellular phenotype.
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