Cargando…
Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks
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). ANR...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701717/ https://www.ncbi.nlm.nih.gov/pubmed/23861667 http://dx.doi.org/10.1371/journal.pgen.1003588 |
_version_ | 1782275700326137856 |
---|---|
author | Holdt, Lesca M. Hoffmann, Steve Sass, Kristina Langenberger, David Scholz, Markus Krohn, Knut Finstermeier, Knut Stahringer, Anika Wilfert, Wolfgang Beutner, Frank Gielen, Stephan Schuler, Gerhard Gäbel, Gabor Bergert, Hendrik Bechmann, Ingo Stadler, Peter F. Thiery, Joachim Teupser, Daniel |
author_facet | Holdt, Lesca M. Hoffmann, Steve Sass, Kristina Langenberger, David Scholz, Markus Krohn, Knut Finstermeier, Knut Stahringer, Anika Wilfert, Wolfgang Beutner, Frank Gielen, Stephan Schuler, Gerhard Gäbel, Gabor Bergert, Hendrik Bechmann, Ingo Stadler, Peter F. Thiery, Joachim Teupser, Daniel |
author_sort | Holdt, Lesca M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3701717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37017172013-07-16 Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks Holdt, Lesca M. Hoffmann, Steve Sass, Kristina Langenberger, David Scholz, Markus Krohn, Knut Finstermeier, Knut Stahringer, Anika Wilfert, Wolfgang Beutner, Frank Gielen, Stephan Schuler, Gerhard Gäbel, Gabor Bergert, Hendrik Bechmann, Ingo Stadler, Peter F. Thiery, Joachim Teupser, Daniel PLoS Genet Research Article 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. Public Library of Science 2013-07-04 /pmc/articles/PMC3701717/ /pubmed/23861667 http://dx.doi.org/10.1371/journal.pgen.1003588 Text en © 2013 Holdt et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Holdt, Lesca M. Hoffmann, Steve Sass, Kristina Langenberger, David Scholz, Markus Krohn, Knut Finstermeier, Knut Stahringer, Anika Wilfert, Wolfgang Beutner, Frank Gielen, Stephan Schuler, Gerhard Gäbel, Gabor Bergert, Hendrik Bechmann, Ingo Stadler, Peter F. Thiery, Joachim Teupser, Daniel Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks |
title | Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks |
title_full | Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks |
title_fullStr | Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks |
title_full_unstemmed | Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks |
title_short | Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks |
title_sort | alu elements in anril non-coding rna at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701717/ https://www.ncbi.nlm.nih.gov/pubmed/23861667 http://dx.doi.org/10.1371/journal.pgen.1003588 |
work_keys_str_mv | AT holdtlescam aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT hoffmannsteve aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT sasskristina aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT langenbergerdavid aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT scholzmarkus aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT krohnknut aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT finstermeierknut aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT stahringeranika aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT wilfertwolfgang aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT beutnerfrank aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT gielenstephan aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT schulergerhard aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT gabelgabor aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT bergerthendrik aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT bechmanningo aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT stadlerpeterf aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT thieryjoachim aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks AT teupserdaniel aluelementsinanrilnoncodingrnaatchromosome9p21modulateatherogeniccellfunctionsthroughtransregulationofgenenetworks |