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 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 Genetic Variation in Androgen Regulation of Ornithine Decarboxylase Gene Expression in Inbred Strains of Mice*

1987 ◽  
Vol 1 (3) ◽  
pp. 266-273 ◽  
Author(s):  
Evie Melanitou ◽  
Deirdre A. Cohn ◽  
C. Wayne Bardin ◽  
Olli A. Jänne
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Ornithine Decarboxylase ◽  
Inbred Strains ◽  
Inbred Strains Of Mice ◽  
Androgen Regulation

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.

scholarly journals In vivo regulation of apolipoprotein A-I gene expression by estradiol and testosterone occurs by different mechanisms in inbred strains of mice.

1991 ◽  
Vol 32 (10) ◽  
pp. 1571-1585
Author(s):  
JJ Tang ◽  
RA Srivastava ◽  
ES Krul ◽  
D Baumann ◽  
BA Pfleger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inbred Strains ◽  
Apolipoprotein A ◽  
Inbred Strains Of Mice ◽  
I Gene

scholarly journals Peptide YY (PYY) Gene Polymorphisms in the 3′-Untranslated Region and Proximal Promoter Regions Regulate Cellular Gene Expression and PYY Secretion and Metabolic Syndrome Traits in Vivo

2009 ◽  
Vol 23 (10) ◽  
pp. 1715-1715
Author(s):  
Pei-an Betty Shih ◽  
Lei Wang ◽  
Stephane Chiron ◽  
Gen Wen ◽  
Caroline Nievergelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Genetic Variation ◽  
Untranslated Region ◽  
Peptide Yy ◽  
Disease Risk ◽  
Association Studies ◽  
Neuroendocrine Cells ◽  
Proximal Promoter ◽  
Common Genetic Variants

ABSTRACT Rationale Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk. Design To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3′-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells. Results Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3′-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3′-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016). Conclusions Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

Genetic variation in femur extrinsic strength in 29 different inbred strains of mice is dependent on variations in femur cross-sectional geometry and bone density

Bone ◽  
2005 ◽  
Vol 36 (1) ◽  
pp. 111-122 ◽  
Author(s):  
Jon E. Wergedal ◽  
Matilda H.-C. Sheng ◽  
Cheryl L. Ackert-Bicknell ◽  
Wesley G. Beamer ◽  
David J. Baylink
Keyword(s):  
Genetic Variation ◽  
Bone Density ◽  
Inbred Strains ◽  
Cross Sectional ◽  
Inbred Strains Of Mice

scholarly journals Slc1a3-2A-CreERT2 mice reveal unique features of Bergmann glia and augment a growing collection of Cre drivers and effectors in the 129S4 genetic background

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lech Kaczmarczyk ◽  
Nicole Reichenbach ◽  
Nelli Blank ◽  
Maria Jonson ◽  
Lars Dittrich ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Phenotypic Diversity ◽  
Expression Patterns ◽  
Cell Types ◽  
Inbred Strains ◽  
Brain Regions ◽  
Genetically Engineered ◽  
Disease Models ◽  
Calcium Indicator ◽  
High Consistency

AbstractGenetic variation is a primary determinant of phenotypic diversity. In laboratory mice, genetic variation can be a serious experimental confounder, and thus minimized through inbreeding. However, generalizations of results obtained with inbred strains must be made with caution, especially when working with complex phenotypes and disease models. Here we compared behavioral characteristics of C57Bl/6—the strain most widely used in biomedical research—with those of 129S4. In contrast to 129S4, C57Bl/6 demonstrated high within-strain and intra-litter behavioral hyperactivity. Although high consistency would be advantageous, the majority of disease models and transgenic tools are in C57Bl/6. We recently established six Cre driver lines and two Cre effector lines in 129S4. To augment this collection, we genetically engineered a Cre line to study astrocytes in 129S4. It was validated with two Cre effector lines: calcium indicator gCaMP5g-tdTomato and RiboTag—a tool widely used to study cell type-specific translatomes. These reporters are in different genomic loci, and in both the Cre was functional and astrocyte-specific. We found that calcium signals lasted longer and had a higher amplitude in cortical compared to hippocampal astrocytes, genes linked to a single neurodegenerative disease have highly divergent expression patterns, and that ribosome proteins are non-uniformly expressed across brain regions and cell types.

scholarly journals Insights into calcium signaling and gene expression in astrocytes uncovered with 129S4 Slc1a3-2A-CreERT2 knock-in mice

2020 ◽  
Author(s):  
Lech Kaczmarczyk ◽  
Nicole Reichenbach ◽  
Nelli Blank ◽  
Maria Jonson ◽  
Lars Dittrich ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Phenotypic Diversity ◽  
Expression Patterns ◽  
Cell Types ◽  
Inbred Strains ◽  
Brain Regions ◽  
Genetically Engineered ◽  
Calcium Currents ◽  
Activity Levels ◽  
Genomic Locus

AbstractGenetic variation is a primary determinant of phenotypic diversity within populations. In laboratory mice, genetic variation has often been regarded as a serious experimental confounder, and thus minimized through inbreeding. However, generalizations of results obtained with inbred strains need to be made with caution. Effects of genetic background on traits need to be controlled, especially when working with complex phenotypes and disease models. Here we compared behavioral parameters of C57Bl/6 – the mouse strain most widely used for biomedical research - with those of 129S4. Our data demonstrate high within-strain and intra-litter behavioral hyperactivity in C57Bl/6. In contrast, 129S4 had relatively consistent activity levels throughout life. This consistency would be advantageous for studying neurodegeneration and aging, when mice need to be analyzed for long periods. However, the majority of mouse models and transgenic tools are on a C57Bl/6 background. We recently established six popular Cre driver lines and two Cre effector lines in 129S4. To augment this collection, we genetically engineered a Cre mouse line to study astrocytes directly in 129S4, which we describe here. For functional validation, it was crossed with two Cre effector lines, each in a different genomic locus, and showed in both cases that it was functional and astrocyte-specific. Calcium currents studied with gCaMP5g-tdTomato were more heterogenous, lasted longer and had a higher amplitude in cortical compared to hippocampal astrocytes. Translatomes studied with RiboTag revealed that some genes thought to mark neurons are also expressed in astrocytes, that genes linked to a single neurodegenerative disease have highly divergent expression patterns, and that ribosome proteins are non-uniformly expressed across brain regions and cell types.

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