Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk

By C. Burd, William R. Jeck, Yan Liu, H. Sanoff, Zefeng Wang, N. Sharpless. PLoS Genetics, 2010

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Human genome-wide association studies have linked single nucleotide polymorphisms (SNPs) on chromosome 9p21.3 near the INK4/ARF (CDKN2a/b) locus with susceptibility to atherosclerotic vascular disease (ASVD). Although this locus encodes three well-characterized tumor suppressors, p16INK4a, p15INK4b, and ARF, the SNPs most strongly associated with ASVD are ∼120 kb from the nearest coding gene within a long non-coding RNA (ncRNA) known as ANRIL (CDKN2BAS). While individuals homozygous for the atherosclerotic risk allele show decreased expression of ANRIL and the coding INK4/ARF transcripts, the mechanism by which such distant genetic variants influence INK4/ARF expression is unknown. Here, using rapid amplification of cDNA ends (RACE) and analysis of next-generation RNA sequencing datasets, we determined the structure and abundance of multiple ANRIL species. Each of these species was present at very low copy numbers in primary and cultured cells; however, only the expression of ANRIL isoforms containing exons proximal to the INK4/ARF locus correlated with the ASVD risk alleles. Surprisingly, RACE also identified transcripts containing non-colinear ANRIL exonic sequences, whose expression also correlated with genotype and INK4/ARF expression. These non-polyadenylated RNAs resisted RNAse R digestion and could be PCR amplified using outward-facing primers, suggesting they represent circular RNA structures that could arise from by-products of mRNA splicing. Next-generation DNA sequencing and splice prediction algorithms identified polymorphisms within the ASVD risk interval that may regulate ANRIL splicing and circular ANRIL (cANRIL) production. These results identify novel circular RNA products emanating from the ANRIL locus and suggest causal variants at 9p21.3 regulate INK4/ARF expression and ASVD risk by modulating ANRIL expression and/or structure.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a32ef4624d75b16c795f25663fa6f9db011f0c3a

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Citations in the corpus

Circular RNAs: diversity of form and function (2014, background): “Intriguingly, expression of circular ANRIL (cANRIL) correlates with atherosclerotic vascular disease risk (Burd et al. 2010).”
Circular RNA: A new star of noncoding RNAs. (2015, background): “More importantly, it is becoming evident that circRNAs may be involved in atherosclerotic vascular disease risk, neurological disorders, prion diseases and cancer [28–30]; are aberrantly expressed in colorectal cancer (CRC) [31] and pancreatic ductal adenocarcinoma (PDAC) (S.”
Circular RNA Expression: Its Potential Regulation and Function (2016, background): “Before this, the only well-studied circRNAs were from the mouse Sex Determining Region Y (Sry) gene, and the Antisense Non-coding RNA in the INK4 locus (ANRIL) and Cerebellar Degeneration-Related protein 1 (CDR1) loci, characterized in 1990, 2010, and 2011, respectively; these were all considered an”
Circular RNAs: analysis, expression and potential functions (2016, background): “Much more recently, a human non-coding RNA named ANRIL was found to have a low abundance transcript capable of circularizing (Burd et al., 2010), and it was also shown that the antisense transcript to the CDR1 locus generated a highly abundant circular isoform that is now extensively studied (Hansen”
Genome regulation by long noncoding RNAs (2012, background): “Mutations in ANRIL are associated with cancer and cardiovascular disease, and lead to aberrant ANRIL transcripts and loss of p16 repression (123).”
The Biogenesis, Functions, and Challenges of Circular RNAs. (2018, background): “This circRNA bound to the essential 60S-preribosomal assembly factor pescadillo homolog 1 (PES1) and suppressed ribosome biogenesis in vascular smooth muscle cells and macrophages, resulting in nucleolar stress and cell death, which are key cellular events in atherosclerosis (Burd et al., 2010; Hold”
CIRI: an efficient and unbiased algorithm for de novo circular RNA identification (2015, background): “Circular RNA (circRNA), one of the latest star RNAs, is an RNA molecule with ends covalently linked in a circle that has been discovered in all domains of life with distinct sizes and sources [3-8].”
Short intronic repeat sequences facilitate circular RNA production (2014, background): “…circular RNAs were serendipitously found over the past 25 years (Nigro et al. 1991; Capel et al. 1993; Cocquerelle et al. 1993; Zaphiropoulos 1997; Burd et al. 2010), but it is becoming increasingly clear that this class of noncoding RNA is much larger than previously appreciated (Salzman et al.…”
Past, present, and future of circRNAs (2019, neutral): “…P450 2C24 gene (Zaphiropoulos, 1996), the human cytochrome P450 gene, the rat androgen-binding protein ( ABP ) gene (Zaphiropoulos, 1997), the human dystrophin gene (Surono et al , 1999), and human Inhibitor of cyclin-dependent kinase 4 (INK4/ARF)-associated non-coding RNA (Burd et al , 2010).”
Long non-coding RNA (LncRNA) and cancer: a new paradigm (2017, background): “CircRNAs such as ci-ankrd52 and circular -ANRIL are examples of circular lncRNAs (19, 20).”
Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types (2012, neutral): “with risk for developing atherosclerosis [16].”
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Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “The ANRIL lncRNA is located upstream of the tumor suppressor locus encoding p16 and p15, mutations or depletion of ANRIL results in the loss of p16 and p15 repression [30,31,32].”
Efficient backsplicing produces translatable circular mRNAs (2015, background): “…(Hansen et al. 2013; Jeck et al. 2013; Memczak et al. 2013; Salzman et al. 2013), among which some are even more abundant than their linear counterparts (Burd et al. 2010; Salzman et al. 2012) and others have novel activity in regulating microRNA function (Hansen et al. 2013; Memczak et al. 2013).”