Association and functional significance of genetic variants present in regulatory elements of SERPINB5 gene in gallbladder cancer

Gene ◽  
2022 ◽  
Vol 808 ◽  
pp. 145989
Author(s):  
Kirti Kumari Sinha ◽  
J. Vinay ◽  
Suryakant Parida ◽  
Shivaram Prasad Singh ◽  
Manjusha Dixit
Keyword(s):  
Gallbladder Cancer ◽  
Genetic Variants ◽  
Functional Significance ◽  
Regulatory Elements

Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival

Tumor Biology ◽  
2015 ◽  
Vol 37 (2) ◽  
pp. 1835-1844 ◽  
Author(s):  
Anu Yadav ◽  
Annapurna Gupta ◽  
Neeraj Rastogi ◽  
Sushma Agrawal ◽  
Ashok Kumar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gallbladder Cancer ◽  
Genetic Variants ◽  
Cancer Susceptibility ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Cancer Stem Cell Markers

scholarly journals Differential functional significance of AP-1 binding sites in the promoter of the gene encoding mouse tissue inhibitor of metalloproteinases-3

1997 ◽  
Vol 324 (2) ◽  
pp. 547-553 ◽  
Author(s):  
Hyungtae KIM ◽  
William D. PENNIE ◽  
Yi SUN ◽  
Nancy H. COLBURN
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Functional Significance ◽  
Regulatory Elements ◽  
Binding Activity ◽  
Model Systems ◽  
Mouse Tissue ◽  
Significant Activity ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor

Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular-matrix-associated protein that suppresses tumorigenicity or invasion in several model systems. We have identified, by in vitro footprinting, six AP-1 (activator protein-1) or AP-1-like binding sites in the mouse TIMP-3 promoter that bind purified c-Jun homodimers. Electrophoretic mobility shift assays revealed that the non-consensus fifth AP-1 binding site (AP-720; nt -720 to -714) had the strongest binding activity for recombinant c-Jun protein, and that the fourth binding site (AP-763; nt -763 to -754) and AP-720 showed strong binding activity for cellular nuclear proteins. Antibody supershift and blocking experiments suggest that AP-720, but not AP-763, binds authentic AP-1 components. Transient transfection reporter assays of deletion constructs showed that the region spanning AP-720 has the highest transcriptional activity, and that sequences 5′ to this region (nt -2846 to -747) may contain negative regulatory elements. The deletion construct containing about 500 nt 5′ to the transcriptional start, but no AP-1 sites, showed lower but significant activity, suggesting both AP-1-dependent and -independent regulation of the mouse TIMP-3 promoter. Mutational inactivation of AP-720 abolished the activity increment that distinguished the reporter construct containing both AP-720 and sixth AP-1 binding site (AP-617; nt -617 to -611) from that containing only AP-617. In summary, we report here that both AP-1 and non-AP-1 elements contribute to activity, with the non-consensus AP-1 site at -720 showing the greatest functional significance among the AP-1 sites.

scholarly journals Identification of atrial fibrillation associated genes and functional non-coding variants

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Antoinette F. van Ouwerkerk ◽  
Fernanda M. Bosada ◽  
Karel van Duijvenboden ◽  
Matthew C. Hill ◽  
Lindsey E. Montefiori ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Target Gene ◽  
Target Genes ◽  
Association Studies ◽  
Regulatory Region ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Cx43 Expression

Abstract Disease-associated genetic variants that lie in non-coding regions found by genome-wide association studies are thought to alter the functionality of transcription regulatory elements and target gene expression. To uncover causal genetic variants, variant regulatory elements and their target genes, here we cross-reference human transcriptomic, epigenomic and chromatin conformation datasets. Of 104 genetic variant regions associated with atrial fibrillation candidate target genes are prioritized. We optimize EMERGE enhancer prediction and use accessible chromatin profiles of human atrial cardiomyocytes to more accurately predict cardiac regulatory elements and identify hundreds of sub-threshold variants that co-localize with regulatory elements. Removal of mouse homologues of atrial fibrillation-associated regions in vivo uncovers a distal regulatory region involved in Gja1 (Cx43) expression. Our analyses provide a shortlist of genes likely affected by atrial fibrillation-associated variants and provide variant regulatory elements in each region that link genetic variation and target gene regulation, helping to focus future investigations.

Association of genetic variants of cancer stem cell gene CD44 haplotypes with gallbladder cancer susceptibility in North Indian population

Tumor Biology ◽  
2013 ◽  
Vol 35 (3) ◽  
pp. 2583-2589 ◽  
Author(s):  
Kiran Lata Sharma ◽  
Anu Yadav ◽  
Annapurna Gupta ◽  
Sonam Tulsayan ◽  
Vijay Kumar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gallbladder Cancer ◽  
Genetic Variants ◽  
Indian Population ◽  
Cancer Susceptibility ◽  
North Indian Population ◽  
Cell Gene ◽  
Stem Cell Gene

scholarly journals A global overview of pleiotropy and genetic architecture in complex traits

2018 ◽  
Author(s):  
Kyoko Watanabe ◽  
Sven Stringer ◽  
Oleksandr Frei ◽  
Maša Umićević Mirkov ◽  
Tinca J.C. Polderman ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Human Genetics ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Multiple Trait ◽  
Current Availability ◽  
Flanking Regions

ABSTRACTAfter a decade of genome-wide association studies (GWASs), fundamental questions in human genetics are still unanswered, such as the extent of pleiotropy across the genome, the nature of trait-associated genetic variants and the disparate genetic architecture across human traits. The current availability of hundreds of GWAS results provide the unique opportunity to gain insight into these questions. In this study, we harmonized and systematically analysed 4,155 publicly available GWASs. For a subset of well-powered GWAS on 558 unique traits, we provide an extensive overview of pleiotropy and genetic architecture. We show that trait associated loci cover more than half of the genome, and 90% of those loci are associated with multiple trait domains. We further show that potential causal genetic variants are enriched in coding and flanking regions, as well as in regulatory elements, and how trait-polygenicity is related to an estimate of the required sample size to detect 90% of causal genetic variants. Our results provide novel insights into how genetic variation contributes to trait variation. All GWAS results can be queried and visualized at the GWAS ATLAS resource (http://atlas.ctglab.nl).

scholarly journals T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk

2020 ◽  
Author(s):  
Dimitre R. Simeonov ◽  
Harikesh S. Wong ◽  
Jessica T. Cortez ◽  
Arabella Young ◽  
Zhongmei Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Regulatory T Cells ◽  
Disease Progression ◽  
Genetic Variants ◽  
Immune Cell ◽  
Disease Risk ◽  
Autoimmune Diabetes ◽  
Cell Subset ◽  
Regulatory Elements

The majority of genetic variants associated with complex human autoimmune diseases reside in enhancers1–3, non-coding regulatory elements that control gene expression. In contrast with variants that directly alter protein-coding sequences, enhancer variants are predicted to tune gene expression modestly and function in specific cellular contexts4, suggesting that small alterations in the functions of key immune cell populations are sufficient to shape disease risk. Here we tested this concept by experimentally perturbing distinct enhancers governing the high affinity IL-2 receptor alpha chain (IL2RA; also known as CD25). IL2RA is an immune regulator that promotes the pro- and anti-inflammatory functions of conventional T cells (Tconvs) and regulatory T cells (Tregs), respectively, and non-coding genetic variants in IL2RA have been linked to multiple autoimmune disorders4. We previously tiled across the IL2RA locus using CRISPR-activation and identified a stimulation-responsive element (CaRE4) with an enhancer that modestly affects the kinetics of IL2RA expression in Tconvs5. This enhancer is conserved across species and harbors a common human SNP associated with protection from Type 1 Diabetes (T1D)5,6. We now identified an additional conserved enhancer, termed CaRE3 enhancer, which modestly affected steady state IL2RA expression in regulatory T cells (Tregs). Despite their seemingly subtle impact on gene expression, the CaRE3 and CaRE4 enhancers had pronounced yet divergent effects on the incidence of diabetes in autoimmune prone animals. Deletion of the conserved CaRE4 enhancer completely protected against autoimmune diabetes even in animals treated with an immunostimulating anti-PD1 checkpoint inhibitor, whereas deletion of the CaRE3 enhancer accelerated spontaneous disease progression. Quantitative multiplexed imaging of the pancreatic lymph nodes (panLNs) revealed that each enhancer deletion preferentially affected the protein expression levels of IL2RA in activated Tconvs or Tregs, reciprocally tuning local competition for IL-2 input signals. In animals lacking the CaRE4 enhancer, skewed IL-2 signaling favored Tregs, increasing their local density around activated Tconvs to strongly suppress emergence of autoimmune effectors. By contrast, in animals lacking the CaRE3 enhancer, IL-2 signals were skewed towards activated Tconvs, promoting their escape from Treg control. Collectively, this work illustrates how subtle changes in gene regulation due to non-coding variation can significantly alter disease progression and how distinct enhancers controlling the same gene can have opposing effects on disease outcomes through cell type-selective activity.

scholarly journals Identifying causal models between genetically regulated methylation patterns and gene expression in healthy colon tissue

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna Díez-Villanueva ◽  
Mireia Jordà ◽  
Robert Carreras-Torres ◽  
Henar Alonso ◽  
David Cordero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Quantitative Trait Loci ◽  
Genetic Variants ◽  
Quantitative Trait ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Colon Tissue ◽  
Tissue Samples ◽  
Trait Loci

Abstract Background DNA methylation is involved in the regulation of gene expression and phenotypic variation, but the inter-relationship between genetic variation, DNA methylation and gene expression remains poorly understood. Here we combine the analysis of genetic variants related to methylation markers (methylation quantitative trait loci: mQTLs) and gene expression (expression quantitative trait loci: eQTLs) with methylation markers related to gene expression (expression quantitative trait methylation: eQTMs), to provide novel insights into the genetic/epigenetic architecture of colocalizing molecular markers. Results Normal mucosa from 100 patients with colon cancer and 50 healthy donors included in the Colonomics project have been analyzed. Linear models have been used to find mQTLs and eQTMs within 1 Mb of the target gene. From 32,446 eQTLs previously detected, we found a total of 6850 SNPs, 114 CpGs and 52 genes interrelated, generating 13,987 significant combinations of co-occurring associations (meQTLs) after Bonferromi correction. Non-redundant meQTLs were 54, enriched in genes involved in metabolism of glucose and xenobiotics and immune system. SNPs in meQTLs were enriched in regulatory elements (enhancers and promoters) compared to random SNPs within 1 Mb of genes. Three colorectal cancer GWAS SNPs were related to methylation changes, and four SNPs were related to chemerin levels. Bayesian networks have been used to identify putative causal relationships among associated SNPs, CpG and gene expression triads. We identified that most of these combinations showed the canonical pathway of methylation markers causes gene expression variation (60.1%) or non-causal relationship between methylation and gene expression (33.9%); however, in up to 6% of these combinations, gene expression was causing variation in methylation markers. Conclusions In this study we provided a characterization of the regulation between genetic variants and inter-dependent methylation markers and gene expression in a set of 150 healthy colon tissue samples. This is an important finding for the understanding of molecular susceptibility on colon-related complex diseases.

scholarly journals Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

2021 ◽  
Author(s):  
Bryan J. Matthews ◽  
David J Waxman
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Sex Differences ◽  
Genetic Variants ◽  
Mouse Liver ◽  
Regulatory Elements ◽  
Individual Variability ◽  
Sex Bias ◽  
Mouse Strains ◽  
Strain Dependent

Sex differences in gene expression are widespread in the liver, where a large number of autosomal factors act in tandem with growth hormone signaling to regulate individual variability of sex differences in liver metabolism and disease. Here, we compare hepatic transcriptomic and epigenetic profiles of mouse strains C57Bl/6J and CAST/EiJ, representing two subspecies separated by 0.5-1 million years of evolution, to elucidate the actions of genetic factors regulating liver sex differences. We identify 144 protein coding genes and 78 lncRNAs showing strain-conserved sex bias; many have gene ontologies relevant to liver function, are more highly liver-specific and show greater sex bias, and are more proximally regulated than genes whose sex bias is strain-dependent. The strain-conserved genes include key growth hormone-dependent transcriptional regulators of liver sex bias; however, three other transcription factors, Trim24 , Tox , and Zfp809, lose sex-biased expression in CAST/EiJ mouse liver. To elucidate these strain specificities in expression, we characterized the strain-dependence of sex-biased chromatin opening and enhancer marks at cis regulatory elements (CREs) within expression quantitative trait loci (eQTL) regulating liver sex-biased genes. Strikingly, 208 of 286 eQTLs with strain-specific, sex-differential effects on expression were associated with a complete gain, loss, or reversal of expression sex differences between strains. Moreover, 166 of the 286 eQTLs were linked to the strain-specific gain or loss of localized sex-biased CREs. Remarkably, a subset of these CREs lacked strain-specific genetic variants yet showed coordinated, strain-dependent sex-biased epigenetic regulation. Thus, we directly link hundreds of strain-specific genetic variants to the high variability in CRE activity and expression of sex-biased genes, and uncover underlying genetically-determined epigenetic states controlling liver sex bias in genetically diverse mouse populations.

Sign in / Sign up

Export Citation Format

Share Document