Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA271836 | ENA |
REPOSITORIES: ENA
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Project description:Background The identification and characterization of somatic cancer driver mutations in the noncoding genome remains challenging.
Objective To broadly characterize noncoding driver mutations for pancreatic ductal adenocarcinoma (PDAC).
Design Using mutation calls from whole-genome sequence (WGS) data in PDACs and genome-scale maps of accessible gene regulatory regions in normal- and tumor-derived pancreatic samples, we analyzed enrichment of noncoding mutations in gene regulatory regions relevant to normal- and tumor-derived pancreatic contexts. Functional follow up of potential driver mutations was performed using chromatin interaction analyses, massively parallel reporter assays (MPRA) and targeted analysis of selected noncoding somatic mutations.
Results We first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3,614 noncoding somatic mutations (NCSMs). Chromatin interaction analysis identified 416 potential target genes and MPRA revealed 178 NCSMs impacting reporter activity (19.45% of those tested). Targeted luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near ZFP36L2 and CDKN2A. For the former, CRISPR interference (CRISPRi) identified ZFP36L2 as a target gene (16.0 - 24.0% reduced expression, P = 0.023-0.0047), and growth inhibition after overexpression of ZFP36L2 (4.1 - 14.1-fold reduction, P = 6.0x10-4 - 3.2x10-3) implicates a possible tumor suppressor function.
Conclusion Our integrative approach provides a catalog of potential noncoding driver mutations and nominates ZFP36L2 as a novel PDAC driver gene with a likely tumor suppressor function.
2025-07-23 | MSV000098624 | MassIVE
Project description:<p>BRCA1 mutations are a hallmark of hereditary ovarian cancer, strongly linked to deficiencies in homologous recombination (HR) DNA repair and impaired DNA replication fork protection. However, its roles in cancer progression beyond maintaining genomic integrity remain poorly understood. Through metabolomics approaches, we found BRCA1-deficiency strikingly increased choline metabolism. Loss of BRCA1 promotes choline uptake through upregulating choline transporter-like protein 4 (CTL4). BRCA1 directly binds and recruits EZH2-mediated H3K27Me3 deposition to CTL4 promoter. CTL4 was therefore overexpressed in ovarian cancer tissues with BRCA1 mutations. Furthermore, BRCA1-deficiency significantly promotes ovarian cancer invasion, while inhibition of CTL4 reverses the high metastatic potential of BRCA1-deficient ovarian cancer cells, suggesting the functionality and specificity of CTL4 as a therapeutic target. Additionally, we discovered that phosphocholine, the choline metabolite increased by CTL4 overexpression, interacted with and stabilized the epithelial-to-mesenchymal transition inducer FAM3C in BRCA1-deficient ovarian cancer cells. Importantly, we identified a potent CTL4 inhibitor, DT-13, which significantly reduces choline metabolism and effectively suppresses metastasis in BRCA1-deficient ovarian cancers. Therefore, our study uncovers a mechanism underlying metastasis in BRCA1-deficient cancers and identifies CTL4 as a therapeutic target for metastatic ovarian cancer patients with BRCA1 mutations.</p>
2026-05-15 | MTBLS12245 | MetaboLights
Project description:Genome-wide analysis of long noncoding RNA expression profile in colorectal cancer
| PRJNA354959 | ENA
Project description: Not available
| S-EPMC2531291 | biostudies-literature
Project description:We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3’ and/or 5’ end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5’ differences and in support of this we report that a 5’ isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5’ isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes
2014-08-06 | GSE58734 | GEO
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:Genome-Wide Discovery of Novel Breast Cancer Predisposing Mutations
| PRJNA264560 | ENA
Project description:Genome-wide Discovery of Novel Colon Cancer Predisposing Mutations
| PRJNA264593 | ENA
Project description:Genome-Wide Discovery of Novel Breast Cancer Predisposing Mutations
| PRJNA264559 | ENA
Project description:Genome-wide Discovery of Novel Colon Cancer Predisposing Mutations
| PRJNA264592 | ENA