Dataset Information

Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

ABSTRACT: The INK4/ARF locus at chromosome 9p21 encoding p14ARF, p15INK4B and p16INK4A is a major tumor suppressor locus, constituting an important barrier for tumor growth. It is frequently inactivated in cancers, especially in urothelial carcinoma (UC). In addition to deletions and DNA hypermethylation, further epigenetic mechanisms might underlie its repression. One candidate factor is the long noncoding RNA ANRIL, which recruits Polycomb proteins (PcG) to regulate expression of target genes in cis and trans. We observed ANRIL overexpression in many UC tissues and cell lines mainly resulting from upregulation of 3'-truncated isoforms. However, aberrant ANRIL expression was neither associated with repression of INK4/ARF genes nor with proliferation activity or senescence. We wondered whether truncated ANRIL isoforms exhibit altered properties resulting in loss of function in cis. We excluded delocalization and performed RNA immunoprecipitation demonstrating interaction between full length or truncated ANRIL and PcG protein CBX7, but not SUZ12 of PRC2. Our data indicate that ANRIL in UC cells may not interact with PRC2, which is central for initializing gene repression. Thus, tissue-specific binding activities between ANRIL and PcG proteins may determine the regulatory function of ANRIL. In conclusion, ANRIL does not play a major role in repression of the INK4/ARF locus in UC.

SUBMITTER: Hoffmann MJ

PROVIDER: S-EPMC5932551 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

Hoffmann Michèle J MJ Dehn Judith J Droop Johanna J Niegisch Günter G Niedworok Christian C Szarvas Tibor T Schulz Wolfgang A WA

Non-coding RNA 20151217 3

The INK4/ARF locus at chromosome 9p21 encoding p14ARF, p15INK4B and p16INK4A is a major tumor suppressor locus, constituting an important barrier for tumor growth. It is frequently inactivated in cancers, especially in urothelial carcinoma (UC). In addition to deletions and DNA hypermethylation, further epigenetic mechanisms might underlie its repression. One candidate factor is the long noncoding RNA ANRIL, which recruits Polyc ...[more]

PMID: 29861427

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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.

Dataset Information

Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

Publications

Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

Similar Datasets

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