Alu Elements in ANRIL Non-coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions Through Trans-regulation of Gene Networks

Overview

Journal PLoS Genet

Specialty Genetics

Date 2013 Jul 18

PMID 23861667

Citations 211

Authors

Lesca M Holdt

Steve Hoffmann

Kristina Sass

David Langenberger

Markus Scholz

Knut Krohn

Knut Finstermeier

Anika Stahringer

Wolfgang Wilfert

Frank Beutner

Stephan Gielen

Gerhard Schuler

Gabor Gabel

Hendrik Bergert

Ingo Bechmann

Peter F Stadler

Joachim Thiery

Daniel Teupser

Affiliations

Soon will be listed here.

Abstract

The chromosome 9p21 (Chr9p21) locus of coronary artery disease has been identified in the first surge of genome-wide association and is the strongest genetic factor of atherosclerosis known today. Chr9p21 encodes the long non-coding RNA (ncRNA) antisense non-coding RNA in the INK4 locus (ANRIL). ANRIL expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which ANRIL regulates target-genes in trans, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, trans-regulation was dependent on Alu motifs, which marked the promoters of ANRIL target genes and were mirrored in ANRIL RNA transcripts. ANRIL bound Polycomb group proteins that were highly enriched in the proximity of Alu motifs across the genome and were recruited to promoters of target genes upon ANRIL over-expression. The functional relevance of Alu motifs in ANRIL was confirmed by deletion and mutagenesis, reversing trans-regulation and atherogenic cell functions. ANRIL-regulated networks were confirmed in 2280 individuals with and without coronary artery disease and functionally validated in primary cells from patients carrying the Chr9p21 risk allele. Our study provides a molecular mechanism for pro-atherogenic effects of ANRIL at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs.

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