Effect of acute ethanol on medidal prefrontal cortex across BXD genetic mapping panel and progenitors.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE28515 | GEO | 2011/12/01
SECONDARY ACCESSION(S): PRJNA138977
REPOSITORIES: GEO
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Project description:In order to elucidate the molecular mechanisms underlying individual variation in sensitivity to ethanol we profiled the prefrontal cortex transcriptomes of two inbred strains that exhibit divergent responses to acute ethanol, the C57BL6/J (B6) and DBA/2J (D2) strains, as well as 27 members of the BXD recombinant inbred panel, which was derived from a B6 x D2 cross. With this dataset we were able to identify several gene co-expression networks that were robustly altered by acute ethanol across the BXD panel. These ethanol-responsive gene-enriched networks were heavily populated by genes regulating synaptic transmission and neuroplasticity, and showed strong genetic linkage to discreet chromosomal loci. Network-based measurements of node importance identified several hub genes as established regulators of ethanol response phenotypes, while other hubs represent novel candidate modulators of ethanol responses. Animals were injected intraperitoneally (IP) with saline or 1.8 g/kg of ethanol. As part of a parallel study of ethanol induced anxiolysis, all mice underwent behavioral testing that included 15 minutes of restraint in a 50 mL conical tube followed by 10 minutes in a light-dark chamber. Mice were killed by cervical dislocation four hours following IP injection. Immediately thereafter, brains were extracted and chilled for 1 minute in iced phosphate buffer before being microdissected into 8 constituent regions, including the medial prefrontal cortex. Samples were randomly assigned to batch groups prior to total RNA extraction, cRNA synthesis and hybridization. Each microarray represent a pooling of 4-5 animals.
2011-12-01 | E-GEOD-28515 | biostudies-arrayexpress
Project description:Ethanol’s anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanol’s acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target Nin alternative splicing, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and that Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified 8 differentially utilized exons and significant exon-skipping events between the strains, including 3 novel splicing events in the 3’ end of the Nin gene that were specific to the D2 strain. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression between B6 and D2 mice, thus contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work contributes to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder.
2024-08-19 | GSE274854 | GEO
Project description:We sequenced dorsal root ganglia mRNA from 25 BXD recombinant inbred mouse strains to determine their variation in gene expression.
2015-06-11 | GSE69374 | GEO
Project description:Individual genetic variation affects gene expression and cell phenotype by acting within complex molecular circuits, but this relationship is still largely unknown. Here, we combine genomic and meso-scale profiling with novel computational methods to detect genetic variants that affect the responsiveness of gene expression to stimulus (responsiveness QTLs) and position them in circuit diagrams. We apply this approach to study individual variation in transcriptional responsiveness to three different pathogen components in the model response of primary bone marrow dendritic cells (DCs) from recombinant inbred mice strains. We show that reQTLs are common both in cis (affecting a single target gene) and in trans (pleiotropically affecting co-regulated gene modules) and are specific to some stimuli but not others. Leveraging the stimulus-specific activity of reQTLs and the differential responsiveness of their associated targets, we show how to position reQTLs within the context of known pathways in this regulatory circuit. For example, we find that a pleiotropic trans-acting genetic factor in chr1:129-165Mb affects the responsiveness of 35 anti-viral genes only during an anti-viral like stimulus. Using RNAi we uncover RGS16 the likely causal gene in this interval, and an activator of the antiviral response. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in other complex circuits in primary mammalian cells. The transcriptional response of DCs to pathogen components in the context of the mouse BXD recombinant inbred lines. We isolated DCs from individual age-synchronized female mice of different BXD and parental strains. We measured 30 global transcription profiles in resting and stimulated DCs from two parental strains (B6 and D2) and six BXD strains. We used bone marrow derived primary DCs from a panel of recombinant inbred (RI) BXD mice derived from a cross of the parental C57BL/6J (B6) and DBA/2J (D2) strains. We measured transcriptional responses in DCs from each of two parental strains and 6 BXD strains stimulated by three ligands of Toll-like receptors: LPS (TLR4 ligand), Pam3CSK ('PAM', TLR2 ligand) and poly IC (TLR3/RIG-I ligand).
2013-03-17 | E-GEOD-40452 | biostudies-arrayexpress
Project description:We sequenced dorsal root ganglia mRNA from 25 BXD recombinant inbred mouse strains to determine their variation in gene expression. Dorsal root ganglia mRNA profiles of recombinant inbred mouse strains
2015-06-11 | E-GEOD-69374 | biostudies-arrayexpress
Project description:Purpose: The goal of the present study is to provide an independent assessment of the retinal transcriptome signatures of the C57BL/6J (B6) and DBA/2J (D2) mice and to enhance existing microarray datasets for accurately defining the allelic differences in the BXD recombinant inbred strains. Methods: Retinas from both B6 and D2 mice (3 of each) were used for the RNA-seq analysis. Transcriptome features were examined for both strains. Differentially expressed genes between the 2 strains were identified and bioinformatic analysis was performed to analyze the transcriptome differences between B6 and D2 strains, including Gene ontology (GO) analysis, Phenotype and Reactome enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The RNA-seq data were then directly compared with one of the microarray datasets (DoD Retina Normal Affy MoGene 2.0 ST RMA Gene Level Microarray Database) hosted on GeneNetwork (www.genenetwork.org). Results: RNA-seq provided an in-depth analysis of the transcriptome of the B6 and D2 retina with a total of more than 30,000,000 reads per sample. Over 70% of the reads were uniquely mapped, resulting in a total of 18,100 gene counts for all 6 samples. 1,665 genes were differentially expressed, with 858 of these more highly expressed in B6 and 807 more highly expressed in D2. Several molecular pathways were differentially active between the two strains, including the retinoic acid metabolic process, endoplasmic reticulum lumen, extracellular matrix organization, and PI3K-Akt signaling pathway. The most enriched KEGG pathways were the pentose and glucuronate interconversions pathway, the cytochrome P450 pathway, protein digestion and absorption pathway and the ECM-receptor interaction pathway. Each of these pathways had a more than 4-fold enrichment. The DoD normal retina microarray database provided expression profiling for 26,191 annotated transcripts for B6 mouse, D2 mouse and 53 BXD strains. A total of 13,793 genes in this microarray dataset were comparable to the RNA-seq dataset. For both B6 and D2, the RNA-seq data and microarray data were highly correlated with each other (Pearson's r = 0.780 for B6 and 0.784 for D2). Our results suggest that the microarray dataset can reliably detect differentially expressed genes between the B6 and D2 retinas, with a positive predictive value of 45.6%, and a negative predictive value of 93.6%. Examples of true positive and false positive genes are provided. Conclusions: Retinal transcriptome features of B6 and D2 mouse strains provide a useful reference for a better understanding of the mouse retina. Generally, the microarray database presented on GeneNetwork shows good agreement with the RNA-seq data, while we note that any allelic difference between B6 and D2 should be verified with the latter.
2019-05-31 | GSE127942 | GEO
Project description:The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large-scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive single-nucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 41 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. CONCLUSION: The data are available through a public web-based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross-tissue, and cross-species comparisons, as well as testing of a broad array of hypotheses.
2009-08-06 | GSE17522 | GEO
Project description:Genetically diverse pluripotent stem cells (PSCs) display varied, heritable responses to differentiation cues in the culture environment. By harnessing these disparities through derivation of embryonic stem cells (ESCs) from the BXD mouse genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, we demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. Upon transition to formative pluripotency using epiblast-like cells (EpiLCs), B6 quickly dissolves naïve networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naïve pluripotency with little bias in differentiation. Genetic mapping identifies 6 major trans-acting loci co-regulating chromatin accessibility and gene expression in ESCs and EpiLCs, indicating a common regulatory system impacting cell state transition. These loci distally modulate occupancy of pluripotency factors, including TRIM28, P300, and POU5F1, at hundreds of regulatory elements. One trans-acting locus on Chr 12 primarily impacts chromatin accessibility in ESCs; while in EpiLCs the same locus subsequently influences gene expression, suggesting early chromatin priming. Consequently, the distal gene targets of this locus are enriched for neurogenesis genes and were more highly expressed when cells carried B6 haplotypes at this Chr 12 locus, supporting genetic regulation of biases in cell fate. Spontaneous formation of embryoid bodies validated this with B6 showing a propensity towards neuroectoderm differentiation and D2 towards definitive endoderm, confirming the fundamental importance of genetic variation influencing cell fate decisions.
2021-10-05 | GSE164935 | GEO
Project description:The immune system plays a pivotal role in susceptibility to and progression of a variety of diseases. Due to its strong genetic basis, heritable differences in immune function may contribute to differential disease susceptibility between individuals. Genetic reference populations, such as the BXD (C57BL/6J X DBA/2J) panel of recombinant inbred (RI) mouse strains, provide a unique model through which to integrate baseline phenotypes in healthy individuals with heritable risk for disease because of the ability to combine data collected from these populations across multiple studies and time. We performed basic immunophenotyping (e.g. percentage of circulating B and T lymphocytes and CD4+ and CD8+ T cell subpopulations) in peripheral blood of healthy mice from 41 BXD RI strains to define the phenotypic variation in this model system and to characterize the genetic architecture that unlerlies these traits. Significant QTL models that explained the majority (50-77%) of phenotypic variance were derived for each trait and for the T:B cell and CD4+:CD8+ ratios. Combining QTL mapping with spleen gene expression data uncovered two quantitative trait transcripts (QTTs), Ptprk and Acp1, that which are candidates for heritable differences in the relative abundance of helper and cytotoxic T cells. These data will be valuable in extracting genetic correlates of the immune system in the BXD panel. In addition, they will be a useful resource in prospective, phenotype-driven model selection to test hypotheses about differential disease or environmental susceptibility between individuals with baseline differences in the composition of the immune system.
2010-03-31 | GSE19935 | GEO
Project description:Parental and BXD mouse lines were received from Jackson Laboratory and The Oak Ridge National Laboratory. Splenocytes were isolated and stained with anti-CD4 and anti-CD25 antibodies. CD4+ T cells were separated into CD4+CD25+ Treg and CD4+CD25- Th cells. Tregs and Th cell were collected from spleens of 31 BXD recombinant inbred strains and of the parental mouse strains DBA/2J and C57BL/6J. Gene expression was measured by microarrays. The comparative analysis of the transcriptomes from the two cell populations allowed us to identify many novel differentially expressed genes. Furthermore, the analysis of cis- and trans-expression Quantitative Trail Loci (eQTLs) showed that both common and unique regulatory mechanisms are active in the two cell types.
2011-12-15 | E-MTAB-836 | biostudies-arrayexpress