Disease-associated variant in LACC1, a Crohn’s risk gene, acts in T cells to alter gene expression, metabolism and T cell function
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE272811 | GEO | 2024/09/30
REPOSITORIES: GEO
Similar Datasets
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations. HepG2 hepatoma cells were stably infected with TRIBAL1 or no insert carrying lentiviruses
2014-02-14 | E-GEOD-54937 | biostudies-arrayexpress
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations. Transcriptome changes to TRIBAL downregulation (48 h) Huh7 were exposed to non-target or TRIBAL-specific antisense oligonucleotides for 48 h in normal (low glucose DMEM, 10% serum, Pen-Strep)
2014-02-14 | E-GEOD-54956 | biostudies-arrayexpress
Project description:Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) have identified 75 genetic risk loci 2-7, the disease causal mechanism underlying most GWAS risk loci remains largely unknown. A major challenge is how to identify a putative causal disease variant among multiple risk variants at individual GWAS risk locus and functionally link the risk allele to LOAD-relevant cellular phenotypes. Leveraging our recent approach for identifying functional noncoding GWAS risk variants that show allele-specific open chromatin (ASoC), we systematically identified putative causal LOAD risk variants in human iPSC-derived neurons and glia cells, and established a causal link between PICALM risk allele to unappreciated microglia (MG)-specific role of PICALM in lipid droplet (LD) accumulation and phagocytosis. Our ASoC mapping identified functional risk variants for 26 AD risk loci, most of which are MG-specific. At the PICALM locus, the LOAD risk allele of the ASoC SNP rs10792832 altered chromatin accessibility to PU.1 binding and reduced PICALM expression in MG, thereby leading to impaired phagocytosis of Amyloid beta (Aβ) and myelin debris. Interestingly, transcriptomic profiling of MG carrying PICALM risk allele not only supported abnormal phagocytosis but also revealed enrichment of gene pathways related to cholesterol synthesis and LD formation. Further genetic and pharmacological perturbations in MG established the causal link of the PICALM risk allele with PICALM reduction, LD accumulation and phagocytosis deficits. Our work elucidates an MG-specific role of PICALM in regulating lipid/cholesterol accumulation that is potentially linked to AD pathophysiology, providing a functional neurobiological basis for developing novel clinical interventions.
2025-01-30 | GSE263809 | GEO
Project description:Genome-wide association studies (GWAS) have identified a great number of non-coding risk variants for colorectal cancer (CRC). To date, the majority of these variants have not been functionally studied. Identification of allele-specific transcription factor (TF) binding is of great importance to understand regulatory consequences of such variants. A recently developed proteome-wide analysis of disease-associated SNPs (PWAS) enables identification of DNA-TF interactions in an unbiased fashion. Here, we performed a large-scale PWAS studies to comprehensively characterize TF binding related to CRC, which identified 731 allele-specific TF binding at 116 CRC risk loci. This screen identified rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and consequently increaseing DCLK3 expression through a long-range interaction, which promotes cancer progression through enhancing expression of the genes related to epithelial-to-mesenchymal transition (EMT).
2017-02-15 | GSE83968 | 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
Project description:Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.
2024-06-10 | GSE269153 | GEO
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations.
2014-02-14 | GSE54956 | GEO
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations.
2014-02-14 | GSE54937 | GEO
Project description:The mechanism by which rs6983267 at 8q24.21 increases cancer risk is unclear for the lack of protein?coding genes in the region although the variant is strongly associated with cancer pathogenesis. Here we identify long non-coding RNAs (lncRNAs) near the 8q24 region and show that expression of lncRNA CARLo-5 is significantly correlated with the risk allele of the cancer-associated variant rs6883267. We further report that the 8q24 enhancer region including the variant directly interacts with active regulatory region of the lncRNA CARLo-5 promtoer. Finally, we demonstrate that CARLo-5 has an oncogenic function by regulating cell proliferation and cell-cycle. Our data provide new insight of disease-related variants in a gene desert. Comparison and identification of cell cycle-related genes differentially expressed by CARLo-5 knockdown using Nanostring analysis in HCT116 cells.
2014-03-05 | E-GEOD-48877 | biostudies-arrayexpress
Project description:The mechanism by which rs6983267 at 8q24.21 increases cancer risk is unclear for the lack of protein?coding genes in the region although the variant is strongly associated with cancer pathogenesis. Here we identify long non-coding RNAs (lncRNAs) near the 8q24 region and show that expression of lncRNA CARLo-5 is significantly correlated with the risk allele of the cancer-associated variant rs6883267. We further report that the 8q24 enhancer region including the variant directly interacts with active regulatory region of the lncRNA CARLo-5 promtoer. Finally, we demonstrate that CARLo-5 has an oncogenic function by regulating cell proliferation and cell-cycle. Our data provide new insight of disease-related variants in a gene desert.
2014-03-05 | GSE48877 | GEO