Circular ANRIL isoforms switch from repressors to activators of p15/CDKN2B expression during RAF1 oncogene-induced senescence
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ABSTRACT:
PROVIDER: PRJNA602329 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10917021_1.fastq.gz | Fastqsanger.gz | |||
| SRR10917021_2.fastq.gz | Fastqsanger.gz | |||
| SRR10917022_1.fastq.gz | Fastqsanger.gz | |||
| SRR10917022_2.fastq.gz | Fastqsanger.gz | |||
| SRR10917023_1.fastq.gz | Fastqsanger.gz |
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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: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.
| S-EPMC7951966 | biostudies-literature
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:Analyze effect of Raf1 S259A on gene expression in HUVEC Total RNA obtained from HUVEC infected with empty lentiviral vector pLVX-IRES-puro (control) or that expressing human RAF1 WT (WT) or RAF1 S259A (S259A).
2012-12-18 | E-GEOD-42964 | biostudies-arrayexpress
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: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:In this study we performed gene transcription analysis of parental MCF7 cells and MCF7 engineered to overexpress oncoprotein RAF1. We demonstrate that overexpression of RAF1 leads to development of ivasive phenotype.
2017-08-31 | GSE100360 | GEO
Project description:The CDKN2B-AS1 gene, also called ANRIL, is located at the human CDKN2A/B locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The CDKN2B-AS1 gene overlaps a critical region of 125 kb covering the CDKN2B gene. The CDKN2A/B locus encompasses three major tumor suppressors juxtaposed and joined into a p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster. CDKN2A encodes splice variants p16-CDKN2A and p14-ARF, and CDKN2B encodes p15-CDKN2B. ANRIL shares a bidirectional promoter with the p14-ARF gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of ANRIL and tumor suppressor p16-CDKN2A, p15-CDKN2B, and p14-ARF genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes ANRIL, p16-CDKN2A, p15-CDKN2B, and p14-ARF in the great majority of the 17 different cancer types. ANRIL was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of p16-CDKN2A, p15-CDKN2B, and p14-ARF genes. A high positive correlation was identified between levels of expression of ANRIL and the three tumor suppressors. The strongest positive association was observed with p14-ARF (p < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data.
| S-EPMC6789474 | biostudies-literature
Project description:Analyze effect of Raf1 S259A on gene expression in HUVEC
2012-12-18 | GSE42964 | GEO
Project description:Long non-coding RNAs（LncRNAs）have important cellular functions and some have roles in different mechanisms of gene regulation. LncRNA-antisense noncoding RNA in the INK4 locus (ANRIL) were found to affect cell inflammation,Nevertheless, the potential genes related to the inflammatory response regulated by ANRIL remain unclear. In this study, we investigated the potential function of ANRIL in regulating expression and alternative splicing. ANRIL-regulated human umbilical vein endothelial (HUVEC) cell transcriptome achieved by high-throughput RNA sequencing(RNA-seq) was obtained to investigate the potential role of ANRIL. Lipofectamine 2000 was used for plasmid transfection. The gene expression profile and alternative splicing pattern of HUVEC overexpressed by ANRIL were analyzed by RNA-seq and compared with the control group. ANRIL overexpression (ANRIL-OE) widely affects the transcription levels of genes related to inflammatory response, NF-κB pathway, type I interferon-mediated signal transduction pathway, and innate immune response. ANRIL extensively regulates the alternative splicing of hundreds of genes through functions such as gene expression, translation, DNA repair, RNA processing, and NF-κB pathway. Many of these genes have an indispensable role in the inflammatory response. ANRIL regulated inflammatory response may be achieved by regulating alternating splicing and potential transcription, which broadens the understanding of ANRIL-mediated gene regulation mechanisms and clarifies the role of ANRIL in mediating inflammatory response mechanisms.
2023-01-11 | GSE197115 | GEO