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Genetic architecture of host proteins involved in SARS-CoV-2 infection.
Pietzner M, Wheeler E, Carrasco-Zanini J, Raffler J, Kerrison ND, Oerton E, Auyeung VPW, Luan J, Finan C, Casas JP, Ostroff R, Williams SA, Kastenmüller G, Ralser M, Gamazon ER, Wareham NJ, Hingorani AD, Langenberg C
(2020) Nat Commun 11: 6397
MeSH Terms: ABO Blood-Group System, Aptamers, Peptide, Blood Coagulation, COVID-19, Drug Delivery Systems, Female, Gene Expression Regulation, Host-Derived Cellular Factors, Host-Pathogen Interactions, Humans, Internet, Male, Middle Aged, Proteins, Quantitative Trait Loci, SARS-CoV-2
Show Abstract · Added December 18, 2020
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
0 Communities
1 Members
0 Resources
16 MeSH Terms
The GTEx Consortium atlas of genetic regulatory effects across human tissues.
GTEx Consortium
(2020) Science 369: 1318-1330
MeSH Terms: Datasets as Topic, Disease, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Quantitative Trait Loci, Sequence Analysis, RNA
Show Abstract · Added September 15, 2020
The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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1 Members
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10 MeSH Terms
The impact of sex on gene expression across human tissues.
Oliva M, Muñoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, Parsana P, Kasela S, Balliu B, Viñuela A, Castel SE, Mohammadi P, Aguet F, Zou Y, Khramtsova EA, Skol AD, Garrido-Martín D, Reverter F, Brown A, Evans P, Gamazon ER, Payne A, Bonazzola R, Barbeira AN, Hamel AR, Martinez-Perez A, Soria JM, GTEx Consortium, Pierce BL, Stephens M, Eskin E, Dermitzakis ET, Segrè AV, Im HK, Engelhardt BE, Ardlie KG, Montgomery SB, Battle AJ, Lappalainen T, Guigó R, Stranger BE
(2020) Science 369:
MeSH Terms: Chromosomes, Human, X, Disease, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Promoter Regions, Genetic, Quantitative Trait Loci, Sex Characteristics, Sex Factors
Show Abstract · Added September 15, 2020
Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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1 Members
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15 MeSH Terms
A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk.
Liu D, Zhou D, Sun Y, Zhu J, Ghoneim D, Wu C, Yao Q, Gamazon ER, Cox NJ, Wu L
(2020) Cancer Res 80: 4346-4354
MeSH Terms: Age Factors, Case-Control Studies, European Continental Ancestry Group, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Models, Genetic, Pancreatic Neoplasms, Polymorphism, Single Nucleotide
Show Abstract · Added September 15, 2020
Pancreatic cancer is among the most well-characterized cancer types, yet a large proportion of the heritability of pancreatic cancer risk remains unclear. Here, we performed a large transcriptome-wide association study to systematically investigate associations between genetically predicted gene expression in normal pancreas tissue and pancreatic cancer risk. Using data from 305 subjects of mostly European descent in the Genotype-Tissue Expression Project, we built comprehensive genetic models to predict normal pancreas tissue gene expression, modifying the UTMOST (unified test for molecular signatures). These prediction models were applied to the genetic data of 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Thirteen genes showed an association of genetically predicted expression with pancreatic cancer risk at an FDR ≤ 0.05, including seven previously reported genes (, and ) and six novel genes not yet reported for pancreatic cancer risk [6q27: OR (95% confidence interval (CI), 1.54 (1.25-1.89); 13q12.13: OR (95% CI), 0.78 (0.70-0.88); 14q24.3: OR (95% CI), 1.35 (1.17-1.56); 17q12: OR (95% CI), 6.49 (2.96-14.27); 17q21.1: OR (95% CI), 1.94 (1.45-2.58); and 20p13: OR (95% CI): 1.41 (1.20-1.66)]. The associations for 10 of these genes (, and ) remained statistically significant even after adjusting for risk SNPs identified in previous genome-wide association study. Collectively, this analysis identified novel candidate susceptibility genes for pancreatic cancer that warrant further investigation. SIGNIFICANCE: A transcriptome-wide association analysis identified seven previously reported and six novel candidate susceptibility genes for pancreatic cancer risk.
©2020 American Association for Cancer Research.
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1 Members
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12 MeSH Terms
Nuclear Regulation of Wnt/β-Catenin Signaling: It's a Complex Situation.
Anthony CC, Robbins DJ, Ahmed Y, Lee E
(2020) Genes (Basel) 11:
MeSH Terms: Active Transport, Cell Nucleus, Animals, Cell Nucleus, Gene Expression Regulation, Developmental, Humans, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added August 10, 2020
Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway-nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes.
0 Communities
1 Members
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7 MeSH Terms
Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism.
Bayraktar EC, La K, Karpman K, Unlu G, Ozerdem C, Ritter DJ, Alwaseem H, Molina H, Hoffmann HH, Millner A, Atilla-Gokcumen GE, Gamazon ER, Rushing AR, Knapik EW, Basu S, Birsoy K
(2020) Nat Metab 2: 487-498
MeSH Terms: Animals, Cell Line, Cell Proliferation, Cholesterol, Gene Expression Regulation, Golgi Apparatus, Humans, Hyperlipidemias, Lipid Metabolism, Membrane Proteins, Proprotein Convertases, Serine Endopeptidases, Sterol Regulatory Element Binding Proteins, Zebrafish
Show Abstract · Added September 9, 2020
Coessentiality mapping has been useful to systematically cluster genes into biological pathways and identify gene functions. Here, using the debiased sparse partial correlation (DSPC) method, we construct a functional coessentiality map for cellular metabolic processes across human cancer cell lines. This analysis reveals 35 modules associated with known metabolic pathways and further assigns metabolic functions to unknown genes. In particular, we identify C12orf49 as an essential regulator of cholesterol and fatty acid metabolism in mammalian cells. Mechanistically, C12orf49 localizes to the Golgi, binds membrane-bound transcription factor peptidase, site 1 (MBTPS1, site 1 protease) and is necessary for the cleavage of its substrates, including sterol regulatory element binding protein (SREBP) transcription factors. This function depends on the evolutionarily conserved uncharacterized domain (DUF2054) and promotes cell proliferation under cholesterol depletion. Notably, c12orf49 depletion in zebrafish blocks dietary lipid clearance in vivo, mimicking the phenotype of mbtps1 mutants. Finally, in an electronic health record (EHR)-linked DNA biobank, C12orf49 is associated with hyperlipidaemia through phenome analysis. Altogether, our findings reveal a conserved role for C12orf49 in cholesterol and lipid homeostasis and provide a platform to identify unknown components of other metabolic pathways.
0 Communities
1 Members
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14 MeSH Terms
Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells.
Osipovich AB, Stancill JS, Cartailler JP, Dudek KD, Magnuson MA
(2020) Diabetes 69: 1476-1491
MeSH Terms: Animals, Calcium, Cells, Cultured, Diet, High-Fat, Female, Gene Expression Regulation, Glucose, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mitochondria, Overnutrition, Sex Characteristics, Transcriptome
Show Abstract · Added April 28, 2020
A sustained increase in intracellular Ca concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on knockout mice. Excitotoxicity caused β-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca channel blocker. Excitotoxicity, overnutrition, and the combination of both stresses caused similar but distinct alterations in the β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-oxidation, and mitochondrial biogenesis and their key regulator Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca, by altering mitochondrial function and impairing β-cell identity, augments overnutrition-induced β-cell failure.
© 2020 by the American Diabetes Association.
2 Communities
3 Members
0 Resources
15 MeSH Terms
The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes.
Gregory JM, Cherrington AD, Moore DJ
(2020) Diabetes 69: 837-847
MeSH Terms: Animals, Diabetes Mellitus, Type 1, Gene Expression Regulation, Humans, Insulin, Insulin Resistance
Show Abstract · Added April 22, 2020
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality-iatrogenic hyperinsulinemia-principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore normal physiology, health, and life in type 1 diabetes.
© 2020 by the American Diabetes Association.
0 Communities
2 Members
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6 MeSH Terms
Functional Properties of Helicobacter pylori VacA Toxin m1 and m2 Variants.
Caston RR, Sierra JC, Foegeding NJ, Truelock MD, Campbell AM, Frick-Cheng AE, Bimczok D, Wilson KT, McClain MS, Cover TL
(2020) Infect Immun 88:
MeSH Terms: Amino Acid Sequence, Bacterial Proteins, Bacterial Toxins, Gene Expression Regulation, Bacterial, Genetic Variation, Helicobacter Infections, Helicobacter pylori, Humans, Protein Domains, Protein Multimerization, Protein Transport, Vacuoles
Show Abstract · Added April 15, 2020
colonizes the gastric mucosa and secretes a pore-forming toxin (VacA). Two main types of VacA, m1 and m2, can be distinguished by phylogenetic analysis. Type m1 forms of VacA have been extensively studied, but there has been relatively little study of m2 forms. In this study, we generated strains producing chimeric proteins in which VacA m1 segments of a parental strain were replaced by corresponding m2 sequences. In comparison to the parental m1 VacA protein, a chimeric protein (designated m2/m1) containing m2 sequences in the N-terminal portion of the m region was less potent in causing vacuolation of HeLa cells, AGS gastric cells, and AZ-521 duodenal cells and had reduced capacity to cause membrane depolarization or death of AZ-521 cells. Consistent with the observed differences in activity, the chimeric m2/m1 VacA protein bound to cells at reduced levels compared to the binding levels of the parental m1 protein. The presence of two strain-specific insertions or deletions within or adjacent to the m region did not influence toxin activity. Experiments with human gastric organoids grown as monolayers indicated that m1 and m2/m1 forms of VacA had similar cell-vacuolating activities. Interestingly, both forms of VacA bound preferentially to the basolateral surface of organoid monolayers and caused increased cell vacuolation when interacting with the basolateral surface compared to the apical surface. These data provide insights into functional correlates of sequence variation in the VacA midregion (m region).
Copyright © 2020 American Society for Microbiology.
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1 Members
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12 MeSH Terms
Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response.
Yang X, Graff SM, Heiser CN, Ho KH, Chen B, Simmons AJ, Southard-Smith AN, David G, Jacobson DA, Kaverina I, Wright CVE, Lau KS, Gu G
(2020) Diabetes 69: 1219-1231
MeSH Terms: Aging, Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Cell Survival, Diabetes Mellitus, Female, Gene Expression Regulation, Developmental, Homeostasis, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Nerve Tissue Proteins, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex
Show Abstract · Added April 7, 2020
Swi-independent 3a and 3b (Sin3a and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse Sin3a and Sin3b are coproduced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine cell function. Mice with loss of in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca influx of -deficient β-cells. RNA sequencing coupled with candidate chromatin immunoprecipitation assays revealed several genes that could be directly regulated by Sin3a in β-cells, which modulate Ca/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Finally, mice with loss of both and in multipotent embryonic pancreatic progenitors had significantly reduced islet cell mass at birth, caused by decreased endocrine progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed "general" coregulators Sin3a and Sin3b in islet β-cells, with Sin3a being dispensable for differentiation but required for postnatal function and survival.
© 2020 by the American Diabetes Association.
2 Communities
2 Members
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16 MeSH Terms