scholarly journals Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

2021 ◽  
Vol 7 (25) ◽  
pp. eabf9808
Author(s):  
Marten A. Hoeksema ◽  
Zeyang Shen ◽  
Inge R. Holtman ◽  
An Zheng ◽  
Nathan J. Spann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Disease Risk ◽  
Phenotypic Diversity ◽  
Inbred Strains ◽  
Dynamic Responses ◽  
Interleukin 4 ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Inbred Strains Of Mice

Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

scholarly journals Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

2020 ◽  
Author(s):  
Marten A. Hoeksema ◽  
Zeyang Shen ◽  
Inge R. Holtman ◽  
An Zheng ◽  
Nathan Spann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Disease Risk ◽  
Phenotypic Diversity ◽  
Inbred Strains ◽  
Dynamic Responses ◽  
Interleukin 4 ◽  
Enhancer Activity ◽  
Inbred Strains Of Mice ◽  
Mutation Analyses

AbstractMechanisms by which non-coding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million SNPs and InDels provided by five inbred strains of mice on the responses of macrophages to interleukin 4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Remarkably, of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage determining and signal-dependent transcription factors driving late enhancer activation. These studies further revealed mechanisms by which non-coding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

scholarly journals Natural genetic variation affecting transcription factor spacing at regulatory regions is generally well tolerated

2020 ◽  
Author(s):  
Zeyang Shen ◽  
Jenhan Tao ◽  
Gregory J. Fonseca ◽  
Christopher K. Glass
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Binding Sites ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Nucleotide Polymorphisms ◽  
Enhancer Activity ◽  
Single Nucleotide ◽  
Natural Genetic Variation ◽  
Influence Gene Expression

AbstractRegulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Single nucleotide polymorphisms (SNPs) and short insertions and deletions (InDels) can influence gene expression by altering the sequences of TF binding sites. Prior studies also showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of altered TF spacing has not been systematically analyzed in the context of natural genetic variation. Here, we exploit millions of InDels provided by five diverse strains of mice to globally investigate the effects of altered spacing on TF binding and local histone acetylation in macrophages. We find that spacing alterations resulting from InDels are generally well tolerated in comparison to genetic variants that directly alter TF binding sites. These findings have implications for interpretation of non-coding genetic variation and comparative analysis of regulatory elements across species.

scholarly journals A selective inference approach for false discovery rate control using multiomics covariates yields insights into disease risk

2020 ◽  
Vol 117 (26) ◽  
pp. 15028-15035 ◽  
Author(s):  
Ronald Yurko ◽  
Max G’Sell ◽  
Kathryn Roeder ◽  
Bernie Devlin
Keyword(s):  
Gene Expression ◽  
Multiple Testing ◽  
Disease Risk ◽  
Association Studies ◽  
Auxiliary Information ◽  
Primary Data ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Hypothesis Tests ◽  
Selective Inference

To correct for a large number of hypothesis tests, most researchers rely on simple multiple testing corrections. Yet, new methodologies of selective inference could potentially improve power while retaining statistical guarantees, especially those that enable exploration of test statistics using auxiliary information (covariates) to weight hypothesis tests for association. We explore one such method, adaptiveP-value thresholding (AdaPT), in the framework of genome-wide association studies (GWAS) and gene expression/coexpression studies, with particular emphasis on schizophrenia (SCZ). Selected SCZ GWAS associationPvalues play the role of the primary data for AdaPT; single-nucleotide polymorphisms (SNPs) are selected because they are gene expression quantitative trait loci (eQTLs). This natural pairing of SNPs and genes allow us to map the following covariate values to these pairs: GWAS statistics from genetically correlated bipolar disorder, the effect size of SNP genotypes on gene expression, and gene–gene coexpression, captured by subnetwork (module) membership. In all, 24 covariates per SNP/gene pair were included in the AdaPT analysis using flexible gradient boosted trees. We demonstrate a substantial increase in power to detect SCZ associations using gene expression information from the developing human prefrontal cortex. We interpret these results in light of recent theories about the polygenic nature of SCZ. Importantly, our entire process for identifying enrichment and creating features with independent complementary data sources can be implemented in many different high-throughput settings to ultimately improve power.

scholarly journals Polymorphisms in the Interleukin 4, Interleukin 13, and Corresponding Receptor Genes Are Not Associated with Systemic Sclerosis and Do Not Influence Gene Expression

2011 ◽  
Vol 39 (1) ◽  
pp. 112-118 ◽  
Author(s):  
JASPER C.A. BROEN ◽  
PHILLIPE DIEUDE ◽  
MADELON C. VONK ◽  
LORENZO BERETTA ◽  
FRANCISCO D. CARMONA ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
Peripheral Blood ◽  
Pulmonary Complications ◽  
Interleukin 4 ◽  
Nucleotide Polymorphisms ◽  
Myeloid Dendritic Cells ◽  
Blood Leukocytes ◽  
Interleukin 13

Objective.Polymorphisms in the genes encoding interleukin 4 (IL4), interleukin 13 (IL13), and their corresponding receptors have been associated with multiple immune-mediated diseases. Our aim was to validate these previous observations in patients with systemic sclerosis (SSc) and scrutinize the effect of the polymorphisms on gene expression in various populations of peripheral blood leukocytes.Methods.We genotyped a cohort of 2488 patients with SSc and 2246 healthy controls from The Netherlands, Spain, United Kingdom, Italy, Germany, and France. Taqman assays were used to genotype single-nucleotide polymorphisms (SNP) in the following genes: (1) IL4 (−590C>T/rs2243250); (2) IL4 receptor alpha (IL4RA) (Q576R/rs1801275); (3) IL13 (R130Q/rs20541 and −1112C>T/rs1800925); and (4) IL13RA1 (43163G>A/rs6646259). The effect of these polymorphisms on expression of the corresponding genes was assessed using quantitative RT-PCR on RNA derived from peripheral blood B cells, T cells, plasmacytoid dendritic cells, monocytes, and myeloid dendritic cells. We investigated whether these polymorphisms influenced development of pulmonary complications over 15 years in patients with SSc.Results.None of the investigated polymorphisms was associated with SSc or any SSc clinical subtype. We did not observe any effect on transcript levels in the cell subtypes or on development of pulmonary complications.Conclusion.Our data showed that polymorphisms in IL4, IL13, and their receptors do not play a role in SSc and do not influence the expression of their corresponding transcript in peripheral blood cells.

scholarly journals Sex-Specific Associations of Genetically-Predicted Circulating Lipoprotein(a) and Hepatic LPA Gene Expression Levels with Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses

2021 ◽  
Author(s):  
Jakie Guertin ◽  
Yannick Kaiser ◽  
Hasanga Manikpurage ◽  
Nicolas Perrot ◽  
Raphaëlle Bourgeois ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cardiovascular Outcomes ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Men And Women ◽  
Expression Levels ◽  
Lipoprotein A

Background - Elevated Lipoprotein(a) (Lp[a]) levels are associated with coronary artery disease (CAD), ischemic stroke (IS) and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. Methods - To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically-predicted Lp(a) levels (using 27 single nucleotide polymorphisms (SNPs) at the LPA locus) and hepatic LPA expression (using 80 SNPs at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS and CAVS using individual participant data from the UK Biobank: 408,403 participants of European ancestry (37,102, 4283 and 2574 with prevalent CAD, IS and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS and CAVS in was also investigated in EPIC-Norfolk: 18,721 participants (3964, 846 and 424 with incident CAD, IS and CAVS, respectively). Results - Genetically-predicted and plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically-predicted and plasma Lp(a) levels was associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically-predicted LPA expression levels was associated with prevalent CAD and CAVS in men and women, but not with IS. Conclusions - Genetically-predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.

scholarly journals Genetic variation in β-adrenergic receptors in mice: A magnesium effect determined by a single gene

1983 ◽  
Vol 42 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Jasna Markovac ◽  
Robert P. Erickson
Keyword(s):  
Genetic Variation ◽  
Recombinant Inbred ◽  
Adrenergic Receptors ◽  
Recombinant Inbred Lines ◽  
Single Gene ◽  
Inbred Strains ◽  
Inbred Lines ◽  
Inbred Strains Of Mice ◽  
Potent Antagonist ◽  
Β Adrenergic Receptors

SUMMARYGenetic variation in the amount of binding of dihydroalprenolol (a potent antagonist) to hepatocyte β-adrenergic receptors has been observed among inbred strains of mice. This variation is attributed to a differential effect of magnesium on the receptors between the high and low binding strains. Evidence for a single gene controlling the magnesium effect on dihydroalprenolol binding to β-adrenergic receptors was found using recombinant inbred lines between the high and low strains. We suggest the provisional gene symbol Badm.

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