Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease

Abstract

The long non-coding RNA CDKN2B-AS1, commonly referred to as the A ntisense N on-coding R NA in the I NK4 L ocus (ANRIL), is a 3.8-kb-long RNA transcribed from the short arm of human chromosome 9 on p21.3 that overlaps a critical region encompassing three major tumor suppressor loci juxtaposed to the INK4b-ARF-INK4a gene cluster and the methyl-thioadenosine phosphorylase (MTAP) gene. Genome-wide association studies have identified this region with a remarkable and growing number of disease-associated DNA alterations and single nucleotide polymorphisms, which corresponds to increased susceptibility to human disease. Recent attention has been devoted on whether these alterations in the ANRIL sequence affect its expression levels and/or its splicing transcript variation, and in consequence, global cellular homeostasis. Moreover, recent evidence postulates that ANRIL not only can regulate their immediate genomic neighbors in cis, but also has the capacity to regulate additional loci in trans. This action would further increase the complexity for mechanisms imposed through ANRIL and furthering the scope of this lncRNA in disease pathogenesis. In this chapter, we summarize the most recent findings on the investigation of ANRIL and provide a perspective on the biological and clinical significance of ANRIL as a putative biomarker, specifically, its potential role in directing cellular fates leading to cancer and cardiovascular disease.

Fig. 1

Illustration of how the ANRIL transcript may facilitate polycomb repressive complex 1 to compact chromatin structure of the INK4b-ARF-INK4a locus

Fig. 2

Comprehensive transcript map overlapping the human INK/ARF locus determines the assembly of transcripts by long read- and strand-specific RNA sequencing by ISO-Seq. Samples taken for ISO-Seq analysis are from a single prostate invasive carcinoma specimen and compared with the paired normal prostate duct epithelium. Highlighted in red are novel transcript isoforms identified in the tumor specimen when compared to the normal duct epithelium of the prostate