Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans

Nat Commun. 2016 Aug 19;7:12429. doi: 10.1038/ncomms12429.

Abstract

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cell Nucleolus / metabolism
  • Cell Proliferation
  • Chromosomes, Human, Pair 9
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p15 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Cyclin-Dependent Kinase Inhibitor p18 / metabolism
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Macrophages / pathology
  • Muscle, Smooth, Vascular / metabolism
  • Proteins / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Ribosomal / genetics
  • RNA, Ribosomal / metabolism*
  • RNA-Binding Proteins

Substances

  • CDKN2A protein, human
  • CDKN2B antisense RNA, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • PES1 protein, human
  • Proteins
  • RNA, Long Noncoding
  • RNA, Ribosomal
  • RNA-Binding Proteins