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An integrated epigenome and transcriptome analysis to clarify the effect of epigenetic inhibitors in gastrointestinal stromal cells (ChIP-Seq)

ABSTRACT: Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain better insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. Trimethylation of histone H3 lysine 3 (H3K4me3), DNA methylome, and transcriptome in GIST-T1 cells were analyzed by chromatin immunoprecipitation-sequencing (ChIP-seq), Infinium HumanMethylation450 BeacChip, and gene expression microarray. Enrichment of H3K4me3 at transcription start sites (TSSs) is positively correlated with gene expression, while DNA methylation is negatively associated with gene expression in GIST-T1 cells. We found that treatment with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor not only upregulated genes with DNA methylation, but also activated a number of interferon signaling-related genes. ChIP-seq analysis revealed that the drug treatment significantly upregulated H3K4me3 levels at TSS regions as well as retrotransposons including endogenous retroviruses (ERVs). Finally, by utilizing the omics data, we screened epigenetically silenced long non-coding RNA genes, and found that hypermethylation of MEG3 is a frequent event and an indicator of worse outcome in GIST patients. Our data suggest that epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. We also show that epigenome data obtained in this study could be a useful resource to identify novel GIST-related genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171498 | GEO | 2021/06/21

REPOSITORIES: GEO

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An integrated epigenome and transcriptome analysis to clarify the effect of epigenetic inhibitors in gastrointestinal stromal cells (Methylation)

Project description:Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain better insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells. Trimethylation of histone H3 lysine 3 (H3K4me3), DNA methylome, and transcriptome in GIST-T1 cells were analyzed by chromatin immunoprecipitation-sequencing (ChIP-seq), Infinium HumanMethylation450 BeacChip, and gene expression microarray. Enrichment of H3K4me3 at transcription start sites (TSSs) is positively correlated with gene expression, while DNA methylation is negatively associated with gene expression in GIST-T1 cells. We found that treatment with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor not only upregulated genes with DNA methylation, but also activated a number of interferon signaling-related genes. ChIP-seq analysis revealed that the drug treatment significantly upregulated H3K4me3 levels at TSS regions as well as retrotransposons including endogenous retroviruses (ERVs). Finally, by utilizing the omics data, we screened epigenetically silenced long non-coding RNA genes, and found that hypermethylation of MEG3 is a frequent event and an indicator of worse outcome in GIST patients. Our data suggest that epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. We also show that epigenome data obtained in this study could be a useful resource to identify novel GIST-related genes.

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An integrated epigenome and transcriptome analysis to clarify the effect of epigenetic inhibitors in gastrointestinal stromal cells (Expression)

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The expression of hematopoietic progenitor cell antigen CD34 is regulated by DNA methylation in a site-dependent manner in gastrointestinal stromal tumours (GISTs)

Project description:The anatomic site-dependent expression of hematopoietic progenitor cell antigen CD34 is a feature of gastrointestinal stromal tumours (GISTs). The basis for the differential CD34 expression is only incompletely understood. This study aimed at understanding the regulation of CD34 in GISTs and clarification of its site-dependent expression. Two sample sets of primary GISTs were interrogated including 52 fresh-frozen and 134 paraffin-embedded and formalin-fixed specimens. DNA methylation analysis was first performed by HumanMethylation450 BeadChip array in three cell lines, namely GIST-T1, GIST882 and GIST48b, that were derived from gastric and intestinal GISTs, and differentially methylated CpG sites were identified upstream of CD34. The methylation degree was further quantified by pyrosequencing and inversely correlated with CD34 mRNA and protein abundance. The gene's expression could be activated upon induction of DNA hypomethylation with 5-aza-2'-deoxycytidine in GIST-T1 and GIST882 cells. In patient samples, a strong inverse correlation of DNA methylation degree with immunohistochemically evaluated CD34 expression was documented. Both CD34 expression and DNA methylation levels were specific to the tumours' anatomic location and mutation status. A constant decrease in methylation levels was observed ranging from almost 100% hypermethylation in intestinal GISTs from duodenum to hypomethylation in rectum. CD34 was heavily methylated in gastric PDGFRA-mutant GISTs in comparison to hypomethylated KIT-mutant counterparts. Our results strongly suggest an epigenetic control of CD34 expression in GISTs by DNA methylation. Differential methylation and expression of CD34 in GISTs along the gastrointestinal tract axis and in tumours that harbour different gain-of-function mutations suggest the origin from different cell populations in the gastrointestinal tract.

2017-01-24 | GSE93963 | GEO

Array CGH analysis of human gastrointestinal stromal tumors

Project description:Gastrointestinal stromal tumors (GISTs) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. A total of 25 GIST specimens were studied using Human Genome CGH Microarray Kit 105A (G4412A, Agilent). Levels of LINE-1 methylation were analyzed using bisulfite-pyrosequencing. LINE-1 hypomethylation was correlated with risk grade, and high-risk GISTs exhibited lower levels of LINE-1 methylation than low- or intermediate-risk GISTs. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. Our data suggest that LINE-1 hypomethylation correlates with the aggressiveness of GISTs. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations.

2010-06-20 | GSE22185 | GEO

Array CGH analysis of human gastrointestinal stromal tumors

2010-06-20 | E-GEOD-22185 | biostudies-arrayexpress

Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs

Project description:Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood. A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH)-deficiency and global DNA hyper-methylation. Here we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary and strongly up-regulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetic state of the parental tumor, including hyper-methylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibitor, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.

2019-10-16 | GSE107447 | GEO

Integrated Profiling and Immunohistochemistry Analyses Link circ-BRIP1, circ-EPHB4 and Their Host Genes with Imatinib Resistance in Gastrointestinal Stromal Tumors

Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract. The majority of GIST patients eventually develop resistance to imatinib therapy. To identify the responsible mechanisms, we investigated the differentially expressed mRNAs and circRNAs in imatinib-resistant GISTs using SBC ceRNA microarrays. We found that 107 mRNAs and 521 circRNAs were significantly differentially expressed between imatinib-naïve and imatinib-resistant GIST tissue samples. qRT-PCR analyses validated that circ-BRIP1, circ-EPHB4 and circ-RECQL4 and their host genes were upregulated in imatinib-resistant GISTs, and circ-BRIP1, circ-EPHB4, and RECQL4 were associated with imatinib resistance, tumor relapse and progression, and metastasis in GIST patients. The expression levels of circ-BRIP1, circ-EPHB4 and their host genes were also evaluated using TMAs with 150 human GISTs. The expression level of EPHB4 was significantly increased in high-grade GISTs in comparison to low-grade GISTs and correlated with imatinib resistance. Specifically, we first developed a method for high-throughput analysis of the expression of differentially expressed circRNAs by ISH-IHC in a set of FFPE-tissue microarrays in GIST. Our results also suggested a possible role for circ-BRIP1, circ-EPHB4, and their host genes in the progression of GISTs.

2024-11-01 | GSE188700 | GEO

Affymetrix Cytoscan HD 2,600K SNP array data for 9 GISTs

Project description:KIT, PDGFRA, NF1, and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumors (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ~70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, and in 3 of 8 micro GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion, and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.

2017-02-03 | GSE93077 | GEO

Distinct gene expression profiles between overt GIST and miniGIST

Project description:In contrast to the paucity of clinic GIST (Gastrointestinal stromal tumor; 0.0014 % happening rate), there is a more than twenty thousand times higher rate for miniGISTs, about ~30% of human population could be identified to have miniGISTs. Exploring the molecular differences between miniGISTs and overt GISTs will help us to understand the transformation mechanisms along with GIST progression, but C-kit and PDGFRA mutations analysis failed to identify the differences between these two groups. Conclusion: miniGISTs have significant distinct gene expression profile with overt GISTs by both unsupervised and supervised analysis. Our finding indicated that c-kit and DOG1 expression are the very early events in the genesis of miniGIST and overt GIST, and miniGIST is a molecular distinct group with overt GIST. Within our study, we collected six miniGISTs with diameter less than 1cm from autopsies and seven overt GISTs from clinic, performed the first system-wide gene expression profiling of miniGISTs and overt GISTs by 3’end RNA Sequencing, and further compared the expression profiles between these two groups.

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