CDKN2A-specific probe captured RNA-sequencing (RNACap-Seq) (HEK293T MCF7)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE128205 | GEO | 2019/03/13
REPOSITORIES: GEO
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Project description:The CDKN2A/B locus at 9p21.3 contains crucial tumor suppressor (P16, P14, and P15) and oncogenic lncRNA ANRIL genes. This locus is most frequently inactivated in cancer genomes by deletion and DNA methylation. However, the mechanisms coordinately regulating their expression level are far from clear. In the present study, a novel lncRNA, P14AS, was characterized in the antisense strand of the fragment near CDKN2A exon1 in human cell lines using CDKN2A-specific probe captured RNA-sequencing (RNACap-Seq).
2019-03-07 | GSE127905 | GEO
Project description:Long non-coding RNAs (ncRNAs) are major regulators of gene expression and cell fate. The INK4 locus encodes the tumour suppressor proteins p15INK4b, p16INK4a and p14ARF required for cell cycle arrest and whose expression increases during senescence. ANRIL is a ncRNA antisense to the p15 gene. In proliferative cells, ANRIL prevents senescence by repressing INK4 genes through the recruitment of Polycomb-group proteins. In models of replicative and RASval12 oncogene-induced senescence (OIS), the expression of ANRIL and Polycomb proteins decreases, thus allowing INK4 derepression. Here, we found in a model of RAF1 OIS that ANRIL expression rather increases, due in particular to an increased stability. This led us to search for circular ANRIL isoforms, as circular RNAs are rather stable species. We found that the expression of two circular ANRIL increases in several OIS models (RAF1, MEK1 and BRAF). In proliferative cells, they repress p15 expression, while in RAF1 OIS, they promote full induction of p15, p16 and p14ARF expression. Further analysis of one of these circular ANRIL shows that it interacts with Polycomb proteins and decreases EZH2 Polycomb protein localization and H3K27me3 at the p15 and p16 promoters, respectively. We propose that changes in the ratio between Polycomb proteins and circular ANRIL isoforms allow these isoforms to switch from repressors of p15 gene to activators of all INK4 genes in RAF1 OIS. Our data reveal that regulation of ANRIL expression depends on the senescence inducer and underline the importance of circular ANRIL in the regulation of INK4 gene expression and senescence.
2020-12-31 | GSE143957 | GEO
Project description:Coronary artery disease (CAD) is the most common cardiovascular disease and the leading cause of death worldwide. To date, the 9p21.3 locus is the most robust and frequently replicated risk locus of CAD among >90 CAD risk loci identified by GWAS. More than 50 CAD-associated genomic variants were identified at the 9p21.3 CAD locus and many of them are located within a long non-coding gene ANRIL, which was initially referred to as Antisense Non-coding RNA in INK4 Locus. The causal role of ANRIL in CAD and the underlying molecular mechanism are unknown. We used gene expression microarray to identify the downstream target genes of ANRIL and to explore molecular mechanisms by which ANRIL might contribute to the risk development of CAD.
2019-01-16 | GSE117676 | GEO
Project description:ABSTRACT Metastases are often the direct cause of death of patients with pancreatic ductal adenocarcinoma (PDAC). Yet, the role of genomic alterations in mediating tropism and metastasis formation by pancreatic cancer cells is currently unknown. We aimed to identify genomic alterations predisposing colonization of PDAC cells to distant organs and decipher mechanisms enabling this process. Methods: Frequency of genomic alterations was assessed in 2668 local-biopsied compared to 2840 metastatic PDAC samples. Tumorigenic phenotype and transcriptomic profile of manipulated PDAC cells was assessed. Results: The prevalence of genomic alterations was site dependent, with different profiles observed in samples obtained from the pancreas compared to those obtained from the liver, lungs or lymph nodes. Liver metastases were characterized by deletion of the cyclin dependent kinase inhibitors 2A/2B (CDKN2A/B, encoding p16 and p15, respectively). Studies in PDAC cells indicated enhanced growth under liver conditions following p16/15 deletion. The liver is characterized by high ammonia-low glutamine environment, and a transcriptomic assay revealed modulation of glutamine-ammonia pathway-related genes by p15/p16. Accordingly, p15/p16 deletion promoted growth under high ammonia-low glutamine condition, upregulated glutamate-ammonia ligase (GLUL) and downregulated glutaminase 2 (GLS2). Importantly, GLUL-silencing had a more pronounced effect on proliferation of p15/p16-deleted PDAC cells. Conclusion: These data suggest a unique role for genomic alterations in mediating tropism and metastases formation. Among these alterations, p15/16 loss was identified as a promoter of liver metastases and further studies indicated a novel role for p16/15, namely, regulation of glutamine synthesis. These findings may pave the way for the development of novel therapeutic strategies aiming at the prevention of liver metastases formation.
2023-07-06 | GSE154492 | GEO
Project description:CDKN2A-specific probe captured RNA-sequencing (RNACap-Seq) (HEK293T MCF7)
| PRJNA526737 | ENA
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis. Aorta and macrophages from ten C57BL/6.MOLFc4(51Mb)-Ldlr-/- mice and their control C57BL/6-Ldlr-/- were obtained, RNA purified and hybridized to GPL9734 Affimetrix microarrays.
2011-09-30 | E-GEOD-24342 | biostudies-arrayexpress
Project description:Common genetic variants in a 58-kilobase (kb) region of chromosome 9p21, near the CDKN2A/B cell proliferation inhibitor genes, are strongly associated with coronary artery disease (CAD). We previously reported a congenic mouse model harboring an atherosclerosis susceptibility locus in a region of homology with the human 9p21 locus. We now report markedly decreased Cdkn2a (cyclin-dependent kinase inhibitor 2a) mRNA expression in macrophages and increased circulating levels of Ly6Chigh inflammatory monocytes in congenic mice compared to controls. A bone marrow (BM) transplantation study revealed that BM-derived cells from Cdkn2a+/- mice are capable of conferring accelerated atherosclerosis, increased inflammatory monocyte subsets and monocyte proliferation in the Ldlr-/- mouse model. These findings provide a mechanistic link between decreased expression of Cdkn2a transcripts, increased monocyte proliferation, and accelerated atherosclerosis.
2011-10-01 | GSE24342 | GEO
Project description:We use NGS to assess the ability of TALE-guided DNA methyltranferases to make targeted changes to DNA methylation Targeted bisulfite sequencing of cells infected with wild-type or mutant TALE-DNMT constructs directed to the CDKN2A (p16) locus
2015-05-01 | E-GEOD-66456 | biostudies-arrayexpress
Project description:The antisense non-coding RNA in the INK locus (ANRIL), which originates from the CDKN2A/B (INK4-ARF) locus, has been identified as a hotspot for genetic variants associated with cardiometabolic disease including coronary artery disease (CAD) and Type 2 diabetes (T2D). We recently found that ANRIL abundance in human pancreatic islets was increased in donors carrying certain T2D risk-SNPs, and that a T2D risk-SNP located within exon2 of ANRIL conferred reduced beta cell proliferation index, pointing to a role for ANRIL in the regulation of T2D pathogenicity via an impact on insulin secretory capacity. Recent studies in other cell types have found that the balance between linear and circular species of ANRIL is linked to the regulation of cardiovascular disease phenotypes. Less is known about circular ANRIL expression in diabetes-relevant cell types and how their abundance might influence the risk of T2D. Herein, we use high-throughput and divergent primer sequencing of circular RNA in human pancreatic islet cells to quantify and characterize circular isoforms of ANRIL. We identified several circular ANRIL isoforms that are more abundant than linear ANRIL and whose expression was correlated across dozens of individuals. Back-splicing did not occur with equal probability at all ANRIL splice sites. Rather, some specific splice sites were found to have a higher propensity to be involved in back-splicing and are weakly enriched for sequence features known to promote back-splicing. Finally, we found that islets from carriers of the T2D risk allele at rs564398 in exon 2 of ANRIL had a higher ratio of circular ANRIL relative to linear ANRIL compared to protective-allele carriers, and that higher circular:linear ANRIL ratio was associated with a decreased beta cell proliferation index. Together, our study points to the combined involvement of both linear and circular ANRIL species in T2D phenotypes and opens the door for future studies to understand the molecular mechanisms by which ANRIL impacts cellular function in human pancreatic islets.
2022-05-11 | GSE192541 | GEO
Project description:9p21 locus polymorphisms have the strongest correlation with coronary artery disease, but as a non-coding locus, disease connection is enigmatic. The lncRNA ANRIL found in 9p21 may regulate vascular smooth muscle cell (VSMC) phenotype to contribute to disease risk. We observed significant variability in induced pluripotent stem cell-derived VSMCs from patients homozygous for risk versus isogenic knockout or non-risk haplotypes. Sub-populations of risk haplotype cells exhibited variable morphology, proliferation, contraction, and adhesion. When sorted by adhesion, risk VSMCs parsed into synthetic and contractile sub-populations, i.e., weakly adherent and strongly adherent, respectively. >90% of differentially expressed genes co-regulated by haplotype and adhesion were associated with Rho GTPases, i.e., contractility. Weakly adherent sub-populations expressed more short isoforms of ANRIL, and when overexpressed in knockout cells, ANRIL suppressed adhesion, contractility, and αSMA expression. These data are the first to suggest that variable lncRNA penetrance may drive mixed functional outcomes that confound pathology.
2022-08-19 | GSE211144 | GEO