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Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE85467 | GEO | 2016/09/28

SECONDARY ACCESSION(S): PRJNA338604

REPOSITORIES: GEO

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Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity.

Project description:Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.

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Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity [methylation]

Project description:Regulatory elements in cancer remain poorly characterized in primary solid tumors. Here we applied microscale histone modification profiling to delineate the landscape of somatic promoters and super-enhancers in primary gastric adenocarcinoma, analyzing 94 epigenomic profiles of primary tumors, normal tissues, and cell lines

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Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity [SNP]

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Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity [RNA-seq]

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Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity [ChIP-seq]

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Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity

Project description:Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-enhancer Heterogeneity

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Aberrant super-enhancer landscape reveals core transcriptional regulatory circuitry in lung adenocarcinoma.

Project description:Lung adenocarcinoma (LUAD) relies on dysregulated gene expression to sustain its infinite growth and progression. Emerging evidence indicates that aberrant transcriptional program results from core transcriptional regulatory circuitry (CRC) which is driven by super-enhancers (SEs). In this study, by integrating profiles of H3K27Ac chromatin immunoprecipitation sequencing (ChIP-seq) from normal adult lung and LUAD cell lines, we revealed that widespread alterations of the super-enhancer were presence during lung carcinogenesis. With SE-based modeling of regulatory circuits and assessments of transcription factor (TF) dependencies, we reconstructed an interconnected transcriptional regulation network formed by three master TFs, including ELF3, EHF, and TGIF1, all of which promoted each other's expression that confirmed by ChIP-qPCR and western blot. Loss-of function assay revealed that each of them is essential for LUAD cells survival, invasion and metastasis. Meanwhile, the rescue assay also illustrated the transacting transcriptional regulatory circuitry. In addition, the mRNA levels of ELF3, EHF, and TGIF1 were differentially expressed in LUAD tumors and peritumoral tissue. IHC of serial sections revealed that high expressions of CRC (ELF3/EHF/TGIF1-High) were closely associated with high proliferative activity in tumor tissue and poor prognosis on patients with LUAD. Finally, we used small molecular inhibitors to perturb the transcriptional circuitry, also exhibited a prominent anti-cancer effect in vitro. Our findings reveal the mechanism of the transcriptional dysregulation and addiction of LUAD.

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Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer.

Project description:One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized.Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis.We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes.

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Integrative Epigenomic and High-Throughput Functional Enhancer Profiling Reveals Determinants of Enhancer Heterogeneity in Gastric Cancer

Project description:Enhancer variation has been proposed as a major cause of cancer heterogeneity – however, mechanisms driving patient-specific enhancer cartographies remain unclear. Here we applied microscale histone modification profiling to delineate the landscape of enhancers in primary gastric adenocarcinoma, analyzing 132 epigenomic profiles of primary tumors, normal tissues, and cell lines

2021-09-14 | GSE162420 | GEO

Integrative analysis of genomic and epigenomic data reveals underlying super-enhancer-mediated microRNA regulatory network for human bone mineral density.

Project description:Bone mineral density (BMD) is a highly heritable complex trait and is a key indicator for diagnosis and treatment for osteoporosis. In the last decade, numerous susceptibility loci for BMD and fracture have been identified by genome wide association studies (GWAS); however, fine mapping of these loci is challengeable. Here, we proposed a new long-range fine-mapping approach that combined super-enhancers (SEs) and microRNAs (miRNAs) data, which were two important factors in control of cell identity and specific differentiation, with the GWAS summary datasets in cell-type-restricted way. Genome-wide SE-based analysis found that the BMD-related variants were significantly enriched in the osteoblast SE regions, indicative of potential long-range effects of such SNPs. With the SNP-mapped SEs (mSEs), 13 accessible long-range mSE-interacted miRNAs (mSE-miRNAs) were identified by integrating osteoblast Hi-C and ATAC-seq data, including three known bone-related miRNAs (miR-132-3p, miR-212-3p and miR-125b-5p). The putative targets of the two newly identified mSE-miRNAs (miR-548aj-3p and miR-190a-3p) were found largely enriched in osteogenic-related pathway and processes, suggesting that these mSE-miRNAs could be functional in the regulation of osteoblast differentiation. Furthermore, we identified 54 genes with the long-range 'mSE-miRNA' approach, and 24 of them were previously reported to be related to skeletal development. Besides, enrichment analysis found that these genes were specifically enriched in the post-transcriptional regulation and bone formation processes. This study provided a new insight into the approach of fine-mapping of GWAS loci. A tool was provided for the genome-wide SE-based analysis and the detection of long-range osteoblast-restricted mSE-miRNAs (https://github.com/Zheng-Lab-Westlake/Osteo-Fine-Mapp-SNP2SE2miRNA).

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