Homo sapiens
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Project description:9p21 locus polymorphisms have the strongest correlation with coronary artery disease, but as a non-coding locus, disease connection is enigmatic. The lncRNA ANRIL found in 9p21 may regulate vascular smooth muscle cell (VSMC) phenotype to contribute to disease risk. We observed significant variability in induced pluripotent stem cell-derived VSMCs from patients homozygous for risk versus isogenic knockout or non-risk haplotypes. Sub-populations of risk haplotype cells exhibited variable morphology, proliferation, contraction, and adhesion. When sorted by adhesion, risk VSMCs parsed into synthetic and contractile sub-populations, i.e., weakly adherent and strongly adherent, respectively. >90% of differentially expressed genes co-regulated by haplotype and adhesion were associated with Rho GTPases, i.e., contractility. Weakly adherent sub-populations expressed more short isoforms of ANRIL, and when overexpressed in knockout cells, ANRIL suppressed adhesion, contractility, and αSMA expression. These data are the first to suggest that variable lncRNA penetrance may drive mixed functional outcomes that confound pathology.
2022-08-19 | GSE211144 | GEO
Project description:We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-specific” functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27 acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL expression.
| EGAS00001001741 | EGA
Project description:The antisense non-coding RNA in the INK locus (ANRIL), which originates from the CDKN2A/B (INK4-ARF) locus, has been identified as a hotspot for genetic variants associated with cardiometabolic disease including coronary artery disease (CAD) and Type 2 diabetes (T2D). We recently found that ANRIL abundance in human pancreatic islets was increased in donors carrying certain T2D risk-SNPs, and that a T2D risk-SNP located within exon2 of ANRIL conferred reduced beta cell proliferation index, pointing to a role for ANRIL in the regulation of T2D pathogenicity via an impact on insulin secretory capacity. Recent studies in other cell types have found that the balance between linear and circular species of ANRIL is linked to the regulation of cardiovascular disease phenotypes. Less is known about circular ANRIL expression in diabetes-relevant cell types and how their abundance might influence the risk of T2D. Herein, we use high-throughput and divergent primer sequencing of circular RNA in human pancreatic islet cells to quantify and characterize circular isoforms of ANRIL. We identified several circular ANRIL isoforms that are more abundant than linear ANRIL and whose expression was correlated across dozens of individuals. Back-splicing did not occur with equal probability at all ANRIL splice sites. Rather, some specific splice sites were found to have a higher propensity to be involved in back-splicing and are weakly enriched for sequence features known to promote back-splicing. Finally, we found that islets from carriers of the T2D risk allele at rs564398 in exon 2 of ANRIL had a higher ratio of circular ANRIL relative to linear ANRIL compared to protective-allele carriers, and that higher circular:linear ANRIL ratio was associated with a decreased beta cell proliferation index. Together, our study points to the combined involvement of both linear and circular ANRIL species in T2D phenotypes and opens the door for future studies to understand the molecular mechanisms by which ANRIL impacts cellular function in human pancreatic islets.
2022-05-11 | GSE192541 | GEO
Project description:Coronary artery disease (CAD) is the most common cardiovascular disease and the leading cause of death worldwide. To date, the 9p21.3 locus is the most robust and frequently replicated risk locus of CAD among >90 CAD risk loci identified by GWAS. More than 50 CAD-associated genomic variants were identified at the 9p21.3 CAD locus and many of them are located within a long non-coding gene ANRIL, which was initially referred to as Antisense Non-coding RNA in INK4 Locus. The causal role of ANRIL in CAD and the underlying molecular mechanism are unknown. We used gene expression microarray to identify the downstream target genes of ANRIL and to explore molecular mechanisms by which ANRIL might contribute to the risk development of CAD.
2019-01-16 | GSE117676 | GEO
Project description:Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their role in human health and 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 athero-protection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. At the molecular level, circANRIL competes with precursor rRNA (pre-rRNA) for binding to pescadillo homolog 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key athero-protective cell functions within the arterial wall. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring athero-protection, thereby unveiling a therapeutic potential of certain circRNAs in human disease. Analysis of transcriptome-wide expression level in HEK293 cells with stable overexpression of circular ANRIL (n=3) compared to a vector control (n=3).
2016-08-22 | E-GEOD-65392 | biostudies-arrayexpress
Project description:Long non-coding RNAs（LncRNAs）have important cellular functions and some have roles in different mechanisms of gene regulation. LncRNA-antisense noncoding RNA in the INK4 locus (ANRIL) were found to affect cell inflammation,Nevertheless, the potential genes related to the inflammatory response regulated by ANRIL remain unclear. In this study, we investigated the potential function of ANRIL in regulating expression and alternative splicing. ANRIL-regulated human umbilical vein endothelial (HUVEC) cell transcriptome achieved by high-throughput RNA sequencing(RNA-seq) was obtained to investigate the potential role of ANRIL. Lipofectamine 2000 was used for plasmid transfection. The gene expression profile and alternative splicing pattern of HUVEC overexpressed by ANRIL were analyzed by RNA-seq and compared with the control group. ANRIL overexpression (ANRIL-OE) widely affects the transcription levels of genes related to inflammatory response, NF-κB pathway, type I interferon-mediated signal transduction pathway, and innate immune response. ANRIL extensively regulates the alternative splicing of hundreds of genes through functions such as gene expression, translation, DNA repair, RNA processing, and NF-κB pathway. Many of these genes have an indispensable role in the inflammatory response. ANRIL regulated inflammatory response may be achieved by regulating alternating splicing and potential transcription, which broadens the understanding of ANRIL-mediated gene regulation mechanisms and clarifies the role of ANRIL in mediating inflammatory response mechanisms.
2023-01-11 | GSE197115 | GEO
Project description:Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The rs1859962 single nucleotide polymorphism (SNP) part of the 17q24.3 locus is a risk factor for prostate cancer (PCa). It defines a 130kb linkage disequilibrium (LD) block that lies in a ~2Mb gene desert area. Despite a role for the proximal SOX9 gene in PCa development, the functional biology driving the risk of this 17q24.3 risk locus is unknown. In the present study, we integrate genome-wide chromatin landscape datasets, namely epigenomes and chromatin openness from diverse cell-types to identify one PCa specific enhancer within the rs1859962 risk LD block. We reveal that this enhancer is part of a 1Mb chromatin loop with the SOX9 gene in PCa cells. The rs8072254 and rs1859961 SNPs part of this LD block map to this enhancer and impose allele-specific gene expression. The variant allele of rs1859961 directly decreases FoxA1 binding while increasing AP-1 binding compared to the reference allele. This latter is key in driving allele-specific gene expression. Together, our results demonstrate the risk associated with the PCa rs1859962 risk LD block is accounted for by multiple genetic variants mapping to a unique enhancer looping to the SOX9 oncogene. Allele-specific recruitment of the transcription factor AP-1 accounts in part for the increased enhancer activity ascribed to this PCa risk LD block. This further demonstrates that an integrative genomics approach can identify the functional biology disrupted by genetic risk-variants. Examination of histone modification H3K36me3 in the prostate cancer LNCaP cell line under DHT treatment.
2012-06-03 | E-GEOD-35829 | biostudies-arrayexpress
Project description:Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Biological and genetic effects on DNA methylation (DNAm) can influence gene regulation and contribute to complex disease. Herein, we characterize variation in endometrial DNAm and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genome-wide genotype data and methylation at 759,345 DNAm sites in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles and DNAm networks, associated with endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.
2023-09-12 | GSE223817 | GEO
Project description:Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The rs1859962 single nucleotide polymorphism (SNP) part of the 17q24.3 locus is a risk factor for prostate cancer (PCa). It defines a 130kb linkage disequilibrium (LD) block that lies in a ~2Mb gene desert area. Despite a role for the proximal SOX9 gene in PCa development, the functional biology driving the risk of this 17q24.3 risk locus is unknown. In the present study, we integrate genome-wide chromatin landscape datasets, namely epigenomes and chromatin openness from diverse cell-types to identify one PCa specific enhancer within the rs1859962 risk LD block. We reveal that this enhancer is part of a 1Mb chromatin loop with the SOX9 gene in PCa cells. The rs8072254 and rs1859961 SNPs part of this LD block map to this enhancer and impose allele-specific gene expression. The variant allele of rs1859961 directly decreases FoxA1 binding while increasing AP-1 binding compared to the reference allele. This latter is key in driving allele-specific gene expression. Together, our results demonstrate the risk associated with the PCa rs1859962 risk LD block is accounted for by multiple genetic variants mapping to a unique enhancer looping to the SOX9 oncogene. Allele-specific recruitment of the transcription factor AP-1 accounts in part for the increased enhancer activity ascribed to this PCa risk LD block. This further demonstrates that an integrative genomics approach can identify the functional biology disrupted by genetic risk-variants.
2012-06-03 | GSE35829 | GEO
Project description:A major goal of genetics research is to elucidate mechanisms explaining how genetic variation contributes to phenotypic variation. The genetic variants identified in genome-wide association studies (GWASs) generally explain only a small proportion of heritability of phenotypic traits, the so-called missing heritability problem. Recent evidence suggests that additional common variants beyond lead GWAS variants contribute to phenotypic variation; however, their mechanistic underpinnings generally remain unexplored. Herein, we undertake a study of haplotype-specific mechanisms of gene regulation at 8p23.1 in the human genome, a region associated with a number of complex diseases. The FAM167A-BLK locus in this region has been consistently found in the genome-wide association studies (GWASs) of systemic lupus erythematosus (SLE) in all major ancestries. Our haplotype-specific chromatin interaction (Hi-C) experiments, allele-specific enhancer activity measurements, genetic analyses, and epigenome editing experiments revealed that: (1) haplotype-specific long-range chromatin interactions are prevalent in 8p23.1; (2) BLK promoter and cis-regulatory elements cooperatively interact with haplotype-specificity; (3) genetic variants at distal regulatory elements are allele-specific modifiers of the promoter variants at FAM167A-BLK; (4) the BLK promoter interacts with and, as an enhancer-like promoter, regulates FAM167A expression and (5) local allele-specific enhancer activities are influenced by global haplotype structure due to chromatin looping. Although SLE causal variants at the FAM167A-BLK locus are thought to reside in the BLK promoter region, our results reveal that genetic variants at distal regulatory elements modulate promoter activity, changing BLK and FAM167A gene expression and disease risk. Our results suggest that global haplotype-specific 3-dimensional chromatin looping architecture has a strong influence on local allelic BLK and FAM167A gene expression, providing mechanistic details for how regional variants controlling the BLK promoter may influence disease risk.
2022-09-07 | GSE211246 | GEO