Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks
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{"title"=>"Alu Elements in ANRIL Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through Trans-Regulation of Gene Networks", "type"=>"journal", "authors"=>[{"first_name"=>"Lesca M.", "last_name"=>"Holdt", "scopus_author_id"=>"21834186100"}, {"first_name"=>"Steve", "last_name"=>"Hoffmann", "scopus_author_id"=>"24471278600"}, {"first_name"=>"Kristina", "last_name"=>"Sass", "scopus_author_id"=>"22434254200"}, {"first_name"=>"David", "last_name"=>"Langenberger", "scopus_author_id"=>"25635871300"}, {"first_name"=>"Markus", "last_name"=>"Scholz", "scopus_author_id"=>"7202888704"}, {"first_name"=>"Knut", "last_name"=>"Krohn", "scopus_author_id"=>"7202378037"}, {"first_name"=>"Knut", "last_name"=>"Finstermeier", "scopus_author_id"=>"21739407800"}, {"first_name"=>"Anika", "last_name"=>"Stahringer", "scopus_author_id"=>"55805414700"}, {"first_name"=>"Wolfgang", "last_name"=>"Wilfert", "scopus_author_id"=>"12775940500"}, {"first_name"=>"Frank", "last_name"=>"Beutner", "scopus_author_id"=>"23979611000"}, {"first_name"=>"Stephan", "last_name"=>"Gielen", "scopus_author_id"=>"7005725390"}, {"first_name"=>"Gerhard", "last_name"=>"Schuler", "scopus_author_id"=>"7202657026"}, {"first_name"=>"Gabor", "last_name"=>"Gäbel", "scopus_author_id"=>"7005722531"}, {"first_name"=>"Hendrik", "last_name"=>"Bergert", "scopus_author_id"=>"6603408936"}, {"first_name"=>"Ingo", "last_name"=>"Bechmann", "scopus_author_id"=>"7003528377"}, {"first_name"=>"Peter F.", "last_name"=>"Stadler", "scopus_author_id"=>"7102702401"}, {"first_name"=>"Joachim", "last_name"=>"Thiery", "scopus_author_id"=>"55737881700"}, {"first_name"=>"Daniel", "last_name"=>"Teupser", "scopus_author_id"=>"6603802932"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-84880799429", "sgr"=>"84880799429", "pui"=>"369438587", "isbn"=>"1553-7390", "pmid"=>"23861667", "doi"=>"10.1371/journal.pgen.1003588"}, "id"=>"cbb1609a-7269-3f13-92e7-7edc3d2ca8f0", "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.", "link"=>"http://www.mendeley.com/research/alu-elements-anril-noncoding-rna-chromosome-9p21-modulate-atherogenic-cell-functions-through-transre", "reader_count"=>133, "reader_count_by_academic_status"=>{"Unspecified"=>5, "Professor > Associate Professor"=>10, "Researcher"=>40, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>36, "Student > Postgraduate"=>5, "Student > Master"=>17, "Other"=>4, "Student > Bachelor"=>4, "Lecturer"=>2, "Professor"=>8}, "reader_count_by_user_role"=>{"Unspecified"=>5, "Professor > Associate Professor"=>10, "Researcher"=>40, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>36, "Student > Postgraduate"=>5, "Student > Master"=>17, "Other"=>4, "Student > Bachelor"=>4, "Lecturer"=>2, "Professor"=>8}, "reader_count_by_subject_area"=>{"Unspecified"=>8, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>36, "Agricultural and Biological Sciences"=>63, "Medicine and Dentistry"=>17, "Arts and Humanities"=>1, "Neuroscience"=>3, "Physics and Astronomy"=>1, "Computer Science"=>3}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>17}, "Neuroscience"=>{"Neuroscience"=>3}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>63}, "Computer Science"=>{"Computer Science"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>36}, "Unspecified"=>{"Unspecified"=>8}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "Iran"=>1, "United States"=>1, "Norway"=>1, "China"=>1, "Finland"=>1, "Denmark"=>1, "United Kingdom"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1111759"], "description"=>"<p>(A) Chr9p21 haplotype structure (HapMap CEU, r<sup>2</sup>) and core atherosclerosis region (between rs12555547 and rs1333050). (B) Exons of initially discovered <i>ANRIL</i> transcripts and their relative position in the Chr9p21 region. *A full list of currently annotated <i>ANRIL</i> isoforms is given in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003588#pgen.1003588.s001\" target=\"_blank\">Figure S1B</a>. (C) <i>ANRIL</i> transcripts identified by RACE and PCR amplification (L1-L17). 4 major isoform groups with 4 distinct transcriptions ends were identified. Frequency of exon occurrence/isoform group is color-coded and given in %. <i>ANRIL1-4</i> denote highly expressed consensus transcripts harbouring exons found in >50% transcripts of the respective isoform group (red). Dotted lines indicate positions of transcript-specific qRT-PCR assays. (D) Study design of <i>ANRIL</i> expression and association with Chr9p21. (E) Association of <i>ANRIL</i> isoforms with Chr9p21 in human PBMC, whole blood and vascular tissue (effect, % change/risk allele defined by rs10757274, rs2383206, rs2383297, and rs10757278).</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "transcripts", "chr9p21", "transcript", "isoforms"], "article_id"=>739974, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Annotated_ANRIL_transcripts_in_the_Chr9p21_region_transcript_structure_and_association_of_ANRIL_isoforms_with_Chr9p21_genotype_/739974", "title"=>"Annotated <i>ANRIL</i> transcripts in the Chr9p21 region, transcript structure and association of <i>ANRIL</i> isoforms with Chr9p21 genotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111760"], "description"=>"<p>(A) Consensus transcripts of 4 <i>ANRIL</i> isoform groups identified by RACE and PCR (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003588#pgen.1003588.s001\" target=\"_blank\">Figure S1</a>). Dotted lines indicate positions of transcript-specific qRT-PCR assays. (B) RT-PCR confirmation of <i>ANRIL</i> over-expression in stable ANRIL1-4 cell lines. 3–4 cell lines per <i>ANRIL</i> isoform were established, no effect on house-keeping gene expression was found (<i>beta-actin</i> (<i>BA</i>); <i>glyceraldehyde-3-phosphate dehydrogenase</i> (<i>GAPDH</i>)). (C) Heatmap of <i>ANRIL trans</i>-regulated transcripts corresponding to panel B. Transcripts with average down- (<0.5-fold, red) and up- (>2-fold, green) regulation relative to vector control are shown. (D–F) Adhesion of <i>ANRIL</i> over-expressing cell lines to PBS-, Matrigel-, and collagen-coated wells (<i>P</i><0.01 for comparison of ANRIL1, 2, 3, 4 vs. vector control). (G–I) Cell proliferation and metabolic activity determined by (G) absolute cell numbers, (*/<sup># </sup><i>P</i><0.05 for ANRIL2 and ANRIL4 vs. vector control), (H) glucose utilisation, and (I) viability assay. (J–L) Apoptosis determined by (J) AnnexinV-positive cells, (K) caspase activity, and (L) caspase-3 staining. (H–K) <i>P</i><0.05 for ANRIL2 and ANRIL4 vs. vector control. (M–O) Reversal of effects by RNAi against <i>ANRIL</i> (*<i>P</i><0.05; SCR- scrambled control). (D–K) At least triplicate measurements per pool of 3–4 biological replicates were performed. For details on experimental setup and <i>P</i>-values please see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003588#pgen.1003588.s012\" target=\"_blank\">Table S3</a>. (M–O) n = 3/group. Validation of siRNA knock-down is shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003588#pgen.1003588.s006\" target=\"_blank\">Figure S6</a>. Error bars indicate s.e.m.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "regulates", "metabolic"], "article_id"=>739975, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ANRIL_regulates_gene_expression_in_t_rans_and_affects_cell_adhesion_metabolic_activity_proliferation_and_apoptosis_/739975", "title"=>"<i>ANRIL</i> regulates gene expression in t<i>rans</i> and affects cell adhesion, metabolic activity, proliferation, and apoptosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111762"], "description"=>"<p>(A, B) RNA immunoprecipitation (RIP) followed by qRT-PCR demonstrating <i>ANRIL</i> binding to PRC but not to CoREST/REST proteins in (A) ANRIL2 and (B) ANRIL4 cells. Copies of ANRIL relative to input control are given in (A) blue and (B) red, nuclear ncRNA <i>U1</i> (white) was used as negative control. rIgG/mIgG/gIgG- rabbit/mouse/goat IgG controls. Error bars indicate s.e.m. (C,D) SUZ12 binding in promoters of <i>ANRIL</i> up-(green), down-(red), and not (black) regulated genes in (C) vector control cell line and (D) in BGO3 cells (GSM602674). TSS- transcription start site. (E, F) Effect of <i>ANRIL</i> over-expression on (E) SUZ12 and (F) CBX7 binding in promoters of up-regulated genes (vector control- dotted line vs. ANRIL2- straight line). (G) Reversal of <i>ANRIL trans</i>-regulation by RNAi against SUZ12 and CBX7 in ANRIL2 cells. SCR- scrambled siRNA control.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "binds", "prc1", "proteins", "recruits", "cbx7", "suz12", "promoters"], "article_id"=>739977, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ANRIL_binds_to_PRC1_and_2_proteins_and_recruits_CBX7_and_SUZ12_to_promoters_of_target_genes_/739977", "title"=>"<i>ANRIL</i> binds to PRC1 and 2 proteins and recruits CBX7 and SUZ12 to promoters of target genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111764"], "description"=>"<p>(A) DNA motif in promoters (5 kb) of <i>trans</i>-regulated genes representing an Alu-DEIN repeat <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003588#pgen.1003588-Deininger1\" target=\"_blank\">[33]</a>. (B) Number of Alu motifs in promoters of <i>trans</i>- and not regulated transcripts (n per 5 kb). (C) ChIP-seq enrichment of SUZ12 and CBX7 binding distal to Alu motif, demonstrating a specific spatial relation of motif occurrence to PcG protein binding. RPM- reads per million mapped reads, CTR- random DNA control sequence. (D) Motif-associated SUZ12 signal peaks in an independent data set from BGO3 cells. The actual signal peak only becomes apparent, if a multiple matching policy is adopted. (E) Using a strict unique-matches only policy, a substantial signal reduction is seen downstream of the motif. Please note differences in y-axis scaling in (D, E). (F) Secondary RNA structure prediction for ANRIL2 using the Vienna RNA package <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003588#pgen.1003588-Tacker1\" target=\"_blank\">[58]</a>. Within the minimum free energy structure, the Alu-DEIN motif is located in a stem-loop structure (arrow). (G) RIP demonstrating <i>ANRIL</i> binding to histone H3 (H3) and trimethylated lysine 27 of histone 3 (H3K27me3) in ANRIL2 (blue) and ANRIL4 (red) cells. <i>U1</i> was used as negative control. mIgG/rIgG- mouse/rabbit IgG control. Error bars indicate s.e.m.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "alu", "motifs", "promoters", "genes", "rna", "spatial", "pcg"], "article_id"=>739979, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_Alu_motifs_in_promoters_of_ANRIL_trans_regulated_genes_and_ANRIL_RNA_and_their_spatial_relation_to_PcG_protein_binding_/739979", "title"=>"Identification of Alu motifs in promoters of <i>ANRIL trans</i>-regulated genes and <i>ANRIL</i> RNA and their spatial relation to PcG protein binding.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111766"], "description"=>"<p>(A) Cell lines over-expressing variants of <i>ANRIL2</i> (ANRIL2a, 2b, 2c) and <i>ANRIL4</i> (ANRIL4a, 4b) devoid of Alu motif sequences highlighted by boxes. Validation of over-expression using qRT-PCR assays. (B) Reversal of up-regulation (<i>TSC22D3</i>) and (C) down-regulation (<i>COL3A1</i>) of <i>ANRIL</i> target-gene mRNA expression in ANRIL2a-2c and ANRIL4a,4b compared to ANRIL2 and ANRIL4. Reversal of (D) cell adhesion, (E) apoptosis, and (F) proliferation in cell lines over-expressing mutant <i>ANRIL</i> isoforms. (G) Stable cell lines containing mutated forms of the Alu motif in <i>ANRIL2</i>. Positions of nucleotide exchanges (0, 25%, 33%, and 100%) in the 48 base-pair Alu motif are indicated in red. (H,I) Reversal of <i>trans</i>-regulation in mutant cell lines compared to ANRIL2. (J) Cell adhesion, (K) apoptosis, and (L) proliferation in mutant cell lines. (B,C,H,I,F,L) 3–4 biological replicates/isoform.(D,E,J,K) quadruplicate measurements per pool of 2–3 biological replicates. Error bars indicate s.e.m.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "alu", "motif", "rna"], "article_id"=>739981, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pivotal_role_for_Alu_motif_in_ANRIL_RNA_function_/739981", "title"=>"Pivotal role for Alu motif in <i>ANRIL</i> RNA function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111767"], "description"=>"<p>(A) PBMC from carriers of the Chr9p21 CAD-risk allele defined by rs10757274, rs2383206, rs2383297, and rs10757278 (n = 8) showed increased adhesion (<i>P</i> = 0.001) and (B) decreased apoptosis (<i>P</i> = 0.008) compared to cells of carriers of the protective allele (n = 8). (C) Schematic of molecular scaffolding by <i>ANRIL</i> mediated through potential chromatin-RNA interaction by Alu motifs.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "cellular", "cells", "schematic", "molecular", "scaffolding"], "article_id"=>739982, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Validation_of_ANRIL_associated_cellular_effects_in_primary_cells_and_schematic_of_molecular_scaffolding_by_ANRIL_/739982", "title"=>"Validation of <i>ANRIL</i>-associated cellular effects in primary cells and schematic of molecular scaffolding by <i>ANRIL</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111769"], "description"=>"<p>Genes with expression changes of <0.5 and >2 in <i>ANRIL</i> over-expressing cell lines 1–4 compared to vector control were included in the analysis: ANRIL1- n = 893 (<0.5 n = 439/>2 n = 454 compared to control), ANRIL2- n = 2658 (<0.5 n = 1116/>2 n = 1542 compared to control), ANRIL 3- n = 1830 (<0.5 n = 1054/>2 n = 776 compared to control), and ANRIL4- n = 2982 (<0.5 n = 1514/>2 n = 1468 compared to control). <i>P</i>-values for enrichment of <i>trans</i>-regulated genes (<a href=\"http://www.ingenuity.com\" target=\"_blank\">www.ingenuity.com</a>) are given.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "enrichment", "genes", "lines"], "article_id"=>739984, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_set_enrichment_analysis_of_ANRIL_trans_regulated_genes_in_cell_lines_ANRIL1_4_/739984", "title"=>"Gene set enrichment analysis of <i>ANRIL trans</i>-regulated genes in cell lines ANRIL1-4.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111771"], "description"=>"<p>Genes correlated with <i>ANRIL</i> expression (assays <i>Ex1-5</i>, <i>Ex18-19</i>; <i>P</i><0.01, n = 5066) and associated with the Chr9p21 genotype (<i>P</i><0.05, n = 1698) in PBMC (n = 2280) of the Leipzig LIFE Heart Study were included in the analysis. <i>P</i>-values for enrichment of genes (<a href=\"http://www.ingenuity.com\" target=\"_blank\">www.ingenuity.com</a>) are given.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "enrichment", "chr9p21-associated", "genes", "2280", "probands", "leipzig"], "article_id"=>739986, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_set_enrichment_analysis_of_ANRIL_correlated_Chr9p21_associated_genes_in_2280_probands_of_the_Leipzig_LIFE_Heart_Study_/739986", "title"=>"Gene set enrichment analysis of <i>ANRIL</i>-correlated, Chr9p21-associated genes in 2280 probands of the Leipzig LIFE Heart Study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-04 02:34:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1111808", "https://ndownloader.figshare.com/files/1111809", "https://ndownloader.figshare.com/files/1111810", "https://ndownloader.figshare.com/files/1111811", "https://ndownloader.figshare.com/files/1111812", "https://ndownloader.figshare.com/files/1111813", "https://ndownloader.figshare.com/files/1111815", "https://ndownloader.figshare.com/files/1111816", "https://ndownloader.figshare.com/files/1111818", "https://ndownloader.figshare.com/files/1111820", "https://ndownloader.figshare.com/files/1111836", "https://ndownloader.figshare.com/files/1111845", "https://ndownloader.figshare.com/files/1111846", "https://ndownloader.figshare.com/files/1111847", "https://ndownloader.figshare.com/files/1111852", "https://ndownloader.figshare.com/files/1111855"], "description"=>"<div><p>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) <i>antisense non-coding RNA in the INK4 locus</i> (<i>ANRIL</i>). <i>ANRIL</i> expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which <i>ANRIL</i> regulates target-genes <i>in trans</i>, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, <i>trans</i>-regulation was dependent on Alu motifs, which marked the promoters of <i>ANRIL</i> target genes and were mirrored in <i>ANRIL</i> RNA transcripts. <i>ANRIL</i> 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 <i>ANRIL</i> over-expression. The functional relevance of Alu motifs in <i>ANRIL</i> was confirmed by deletion and mutagenesis, reversing <i>trans</i>-regulation and atherogenic cell functions. <i>ANRIL</i>-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 <i>ANRIL</i> at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs.</p></div>", "links"=>[], "tags"=>["genetics", "epigenetics", "gene expression", "Gene function", "Gene networks", "genomics", "Genome expression analysis", "Molecular cell biology", "cell adhesion", "Cell growth", "cardiovascular", "atherosclerosis", "Coronary artery disease", "alu", "elements", "non-coding", "rna", "chromosome", "9p21", "modulate", "atherogenic", "functions", "networks"], "article_id"=>740011, "categories"=>["Medicine", "Biological Sciences"], "users"=>["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 Gäbel", "Hendrik Bergert", "Ingo Bechmann", "Peter F. Stadler", "Joachim Thiery", "Daniel Teupser"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003588.s001", "https://dx.doi.org/10.1371/journal.pgen.1003588.s002", "https://dx.doi.org/10.1371/journal.pgen.1003588.s003", "https://dx.doi.org/10.1371/journal.pgen.1003588.s004", "https://dx.doi.org/10.1371/journal.pgen.1003588.s005", "https://dx.doi.org/10.1371/journal.pgen.1003588.s006", "https://dx.doi.org/10.1371/journal.pgen.1003588.s007", "https://dx.doi.org/10.1371/journal.pgen.1003588.s008", "https://dx.doi.org/10.1371/journal.pgen.1003588.s009", "https://dx.doi.org/10.1371/journal.pgen.1003588.s010", "https://dx.doi.org/10.1371/journal.pgen.1003588.s011", "https://dx.doi.org/10.1371/journal.pgen.1003588.s012", "https://dx.doi.org/10.1371/journal.pgen.1003588.s013", "https://dx.doi.org/10.1371/journal.pgen.1003588.s014", "https://dx.doi.org/10.1371/journal.pgen.1003588.s015", "https://dx.doi.org/10.1371/journal.pgen.1003588.s016"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Alu_Elements_in_ANRIL_Non_Coding_RNA_at_Chromosome_9p21_Modulate_Atherogenic_Cell_Functions_through_Trans_Regulation_of_Gene_Networks/740011", "title"=>"Alu Elements in <i>ANRIL</i> Non-Coding RNA at Chromosome 9p21 Modulate Atherogenic Cell Functions through <i>Trans</i>-Regulation of Gene Networks", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-07-04 02:34:12"}

PMC Usage Stats | Further Information

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Relative Metric

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