title: Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks.
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.
authors.affiliation: LIFE - Leipzig Research Center for Civilization Diseases, Universität Leipzig, Leipzig, Germany.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.forename: Steve
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Kristina
authors.initials: K
authors.lastname: Sass
authors.forename: David
authors.initials: D
authors.lastname: Langenberger
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.forename: Knut
authors.initials: K
authors.lastname: Krohn
authors.forename: Knut
authors.initials: K
authors.lastname: Finstermeier
authors.forename: Anika
authors.initials: A
authors.lastname: Stahringer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wilfert
authors.forename: Frank
authors.initials: F
authors.lastname: Beutner
authors.forename: Stephan
authors.initials: S
authors.lastname: Gielen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuler
authors.forename: Gabor
authors.initials: G
authors.lastname: Gäbel
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bergert
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Peter F
authors.initials: PF
authors.lastname: Stadler
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D063146:Polycomb-Group Proteins; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: C561518:CDKN2B antisense RNA, human; D063146:Polycomb-Group Proteins; D062085:RNA, Long Noncoding