Ontology highlight
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PROVIDER: PRJNA628586 | ENA |
REPOSITORIES: ENA
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Project description:Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
| PRJNA628639 | ENA
Project description:CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumour suppressors. Currently, for most cancers including gastric cancer [GC], mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulphide (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS-deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions.
2021-04-19 | GSE149411 | GEO
Project description:Integration of synthetic CpG Free DNA induces de novo DNAme in the flanking CpG island. Cellular differentiation requires global changes to DNA methylation (DNAme), where it functions to regulate transcription factor and chromatin remodeling activity, and genome interpretation. Here, we describe a simple DNAme engineering approach in pluripotent stem cells (PSCs), extending across large stretches of CpG dense “islands (CGIs).” Integration of synthetic CpG free single-stranded DNA (ssDNA) induces a target CpG Island Methylation Response (CIMR) in multiple PSC lines, Nt2d1 embryonal carcinoma cells, and mouse PSCs, but not in highly methylated CpG Island Methylator Phenotype (CIMP) positive cancer lines. CIMR DNAme at MLH1 spans the CGI, is robustly maintained throughout cellular differentiation, suppresses target gene activity, and sensitizes derived cardiomyocytes and thymic epithelial cells to the chemotherapy cisplatin. Additional CIMR DNAme is reported on at TP53 and ONECUT1 CGIs. Collectively, this new resource enables total CpG Island DNAme engineering in pluripotency and the genesis of novel epigenetic models of development and disease
2023-06-21 | GSE210680 | GEO
Project description:Engineering Pluripotent DNA Methylation by CpG Island Methylation Response (CIMR) to Synthetic CpG-free ssDNA Insertion Cellular differentiation requires global changes to DNA methylation (DNAme), where it functions to regulate transcription factor and chromatin remodeling activity, and genome interpretation. Here, we describe a simple DNAme engineering approach in pluripotent stem cells (PSCs), extending across large stretches of CpG dense “islands (CGIs).” Integration of synthetic CpG free single-stranded DNA (ssDNA) induces a target CpG Island Methylation Response (CIMR) in multiple PSC lines, Nt2d1 embryonal carcinoma cells, and mouse PSCs, but not in highly methylated CpG Island Methylator Phenotype (CIMP) positive cancer lines. CIMR DNAme at MLH1 spans the CGI, is robustly maintained throughout cellular differentiation, suppresses target gene activity, and sensitizes derived cardiomyocytes and thymic epithelial cells to the chemotherapy cisplatin. Additional CIMR DNAme is reported on at TP53 and ONECUT1 CGIs. Collectively, this new resource enables total CpG Island DNAme engineering in pluripotency and the genesis of novel epigenetic models of development and disease
2023-06-21 | GSE210107 | GEO
Project description:Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland. 10 primary posterior fossa ependymomas have been analyzed
2014-03-15 | E-GEOD-55920 | biostudies-arrayexpress
Project description:Background: Constitutional MLH1 epimutations are characterized by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterization of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Methods: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients and 41 healthy controls, were analyzed by Infinium Human Methylation 450K beadchip, and targeted molecular techniques were used to characterize the MLH1 epimutation in carriers and their inheritance pattern. Results: No nucleotide or structural variants were identified in-cis on the epimutated allele in ten carriers, in which intergenerational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Conclusion: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterization is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.
2017-11-28 | GSE107352 | GEO
Project description:Background: Constitutional MLH1 epimutations are characterized by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterization of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Methods: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients and 41 healthy controls, were analyzed by Infinium Human Methylation 450K beadchip, and targeted molecular techniques were used to characterize the MLH1 epimutation in carriers and their inheritance pattern. Results: No nucleotide or structural variants were identified in-cis on the epimutated allele in ten carriers, in which intergenerational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Conclusion: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterization is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.
2017-11-28 | GSE107351 | GEO
Project description:In order to identify other molecular aberrations that may cooperate with IDH1R132MUT in gliomagenesis, we performed CpG-island methylation profiling analysis using MSRE (Tran et al. Front. Neurosci. 3:57. Doi: 10.3389/neuro.15.005.2009) on a subset of IDH1R132MUT and IDH1R132WT GBMs and found a distinct pattern of CpG island hypermethylation that was detected in all GBMs and lower grade gliomas with IDH1R132MUT. While absent from nearly all IDH1R132WT glioma, the methylation pattern in IDH1R132MUT GBMs shows similarity to the recently reported CpG island methylator phenotype (CIMP) found to be tightly associated with IDH1R132MUT gliomas(Noushmehr et al. Cancer Cell, Volume 17, Issue 5, 18 May 2010, Pages 510-522, ISSN 1535-6108, DOI: 10.1016/j.ccr.2010.03.017).
2011-10-25 | GSE28271 | GEO
Project description:Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland.
2014-03-15 | GSE55920 | GEO
Project description:Stability of the CpG island methylator phenotype during glioblastoma progression.
| PRJNA251945 | ENA