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Oncogenic Antisense LncRNA P14AS Regulates Expression of ANRIL through AUF1 Binding

ABSTRACT: 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).

ORGANISM(S): Homo sapiens

PROVIDER: GSE127905 | GEO | 2019/03/07

REPOSITORIES: GEO

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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.

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Oncogenic Antisense LncRNA P14AS Regulates Expression of ANRIL through AUF1 Binding

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