Variation In Transcriptional Response Research Articles

Being African American and Rural: A Double Jeopardy From COVID-19.

Being African American and Rural: A Double Jeopardy From COVID-19.

Variation in transcriptional responses to copper exposure across Daphnia pulex lineages

Copper pollution is pervasive in aquatic habitats and is particularly harmful to invertebrates sensitive to environmental changes such as Daphnia pulex. Mechanisms of toxicity and tolerance to copper are not well understood. We used RNA-sequencing to investigate these mechanisms in three genetically distinct D. pulex clonal lineages with different histories of copper exposure. Upregulated genes after copper exposure were enriched with Gene Ontology (GO) categories involved in digestion, molting and growth, whereas downregulated genes after copper exposure were enriched in the metal-regulatory system, immune response and epigenetic modifications. The three D. pulex clones in our study show largely similar transcriptional patterns in response to copper, with only a total of twenty genes differentially expressed in a single clonal lineages. We also detected lower relative expression of some genes known to be important for copper tolerance, metallothionein and glutathione-S-transferase, in a sensitive lineage sampled from an uncontaminated habitat. Daphnia-specific genes (without orthologs outside the genus) and Daphnia-specific duplications (genes duplicated in the Daphnia lineage) were overrepresented in differentially expressed genes, highlighting an important role for newly emerged genes in tolerating environmental stressors. The results indicate that the D. pulex lineages tested in this study generally respond to copper stress using the same major pathways, but that the more resistant clone with previous copper exposure might be better able to regulate key genes. This finding highlights the important nuances in gene expression among clones, shaped by historical exposure and influencing copper tolerance.

Photosynthetic response to increased irradiance correlates to variation in transcriptional response of lipid-remodeling and heat-shock genes.

Plants have evolved several mechanisms for sensing increased irradiance, involving signal perception by photoreceptors (cryptochromes), and subsequent biochemical (reactive oxygen species, ROS) and metabolic clues to transmit the signals. This results in the increased expression of heat‐shock response genes and of the transcription factor LONG HYPOCOTYL 5 (HY5, mediated by the cryptochrome photoreceptor 1, CRY1). Here, we show the existence of another response pathway in Arabidopsis. This pathway evokes the SPX1‐mediated expression activation of the transcription factor PHR1 and leads to the expression of several galactolipid biosynthesis genes. Gene expression analysis of accessions Col‐0, Ga‐0, and Ts‐1, showed activated expression of the SPX1/PHR1‐mediated gene expression activation pathway acting on galactolipids biosynthesis genes in both Ga‐0 and Col‐0, but not in Ts‐1. The activation of the SPX1/PHR1‐mediated response pathway can be associated with lower photosynthesis efficiency in Ts‐1, compared to Col‐0 and Ga‐0. Besides the accession‐associated activation of the SPX1/PHR1‐mediated response pathway, comparing gene expression in the accessions showed stronger activation of several heat responsive genes in Ga‐0, and the opposite in Ts‐1, when compared to Col‐0, in line with the differences in their efficiency of photosynthesis. We conclude that natural variation in activation of both heat responsive genes and of galactolipids biosynthesis genes contribute to the variation in photosynthesis efficiency in response to irradiance increase.

Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes.

Anthracycline-induced cardiotoxicity (ACT) is a key limiting factor in setting optimal chemotherapy regimes, with almost half of patients expected to develop congestive heart failure given high doses. However, the genetic basis of sensitivity to anthracyclines remains unclear. We created a panel of iPSC-derived cardiomyocytes from 45 individuals and performed RNA-seq after 24 hr exposure to varying doxorubicin dosages. The transcriptomic response is substantial: the majority of genes are differentially expressed and over 6000 genes show evidence of differential splicing, the later driven by reduced splicing fidelity in the presence of doxorubicin. We show that inter-individual variation in transcriptional response is predictive of in vitro cell damage, which in turn is associated with in vivo ACT risk. We detect 447 response-expression quantitative trait loci (QTLs) and 42 response-splicing QTLs, which are enriched in lower ACT GWAS [Formula: see text]-values, supporting the in vivo relevance of our map of genetic regulation of cellular response to anthracyclines.

Reconstructing the Molecular Function of Genetic Variation in Regulatory Networks.

Over the past decade, genetic studies have recognized hundreds of polymorphic DNA loci called response QTLs (reQTLs) as potential contributors to interindividual variation in transcriptional responses to stimulations. Such reQTLs commonly affect the transduction of signals along the regulatory network that controls gene transcription. Identifying the pathways through which reQTLs perturb the underlying network has been a major challenge. Here, we present GEVIN ("Genome-wide Embedding of Variation In Networks"), a methodology that simultaneously identifies a reQTL and the particular pathway in which the reQTL affects downstream signal transduction along the network. Using synthetic data, we show that this algorithm outperforms existing pathway identification and reQTL identification methods. We applied GEVIN to the analysis of murine and human dendritic cells in response to pathogenic components. These analyses revealed significant reQTLs together with their perturbed Toll-like receptor signaling pathways. GEVIN thus offers a powerful framework that renders a comprehensive picture of disease-related DNA loci and their molecular functions within regulatory networks.

Deciphering transcriptome profiles of peripheral blood mononuclear cells in response to PRRSV vaccination in pigs.

BackgroundPorcine reproductive and respiratory syndrome (PRRS) is one of the most economically important viral diseases affecting swine industry worldwide. Despite routine farm vaccination, effective control strategies for PRRS remained elusive which underscores the need for in-depth studies to gain insight into the host immune response to vaccines. The current study aimed to investigate transcriptional responses to PRRS Virus (PRRSV) vaccine in the peripheral blood mononuclear cells (PBMCs) within 3 days following vaccination in German Landrace pigs.ResultsTranscriptome profiling of PBMCs from PRRSV vaccinated and age-matched unvaccinated pigs at right before (0 h), and at 6, 24 and 72 h after PRRSV vaccination was performed using the Affymetrix gene chip porcine gene 1.0 st array. Comparison of PBMCs transcriptome profiles between vaccinated and unvaccinated pigs revealed a distinct host innate immune transcriptional response to PRRSV vaccine. There was a significant temporal variation in transcriptional responses of PRRSV vaccine in PBMCs accounting 542, 2,263 and 357 differentially expressed genes (DEGs) at 6, 24 and 72 h post vaccination, respectively compared to the time point before vaccination (controls). Gene ontology analysis revealed the involvement of these DEGs in various biological process including innate immune response, signal transduction, positive regulation of MAP kinase activity, TRIF-dependent toll-like receptor signaling pathway, T cell differentiation and apoptosis. Immune response specific pathways such as cytokine-cytokine receptor interaction, chemokine signaling pathway, signal transduction, JAK-STAT pathway and regulation, TRAF6 mediated induction of NF-kB and MAPK, the NLRP3 inflammasome, endocytosis and interferon signaling were under regulation during the early stage of PRRSV vaccination. Network enrichment analysis revealed APP, TRAF6, PIN1, FOS, CTNNB1, TNFAIP3, TIP1, CDKN1, SIRT1, ESR1 and HDAC5 as the highly interconnected hubs of the functional network of PRRSV vaccine induced transcriptome changes in PBMCs.ConclusionsThis study showed that a massive gene expression change occurred in PBMCs following PRRSV vaccination in German Landrace pigs. Within first 3 days of vaccine exposure, the highest transcript abundance was observed at 24 h after vaccination compared to that of control. Results of this study suggest that APP, TRAF6, PIN1, FOS, CDKN1A and TNFAIP3 could be considered as potential candidate genes for PRRSV vaccine responsiveness.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2849-1) contains supplementary material, which is available to authorized users.

Transcription of a novel P450 gene varies with some factors (pollutant exposure, temperature, time, and body region) in a marine oligochaete (Thalassodrilides sp.)

Cytochrome P450 (CYP) enzymes play important roles in the metabolism of exogenous compounds such as polycyclic aromatic hydrocarbons (PAHs). A novel, full-length CYP gene (CYP4V30) was identified in the oligochaete Thalassodrilides sp. CYP4V30 mRNA expression was studied in worms exposed to PAH-polluted (Σ16PAHs; 37441ng/g dry weight) or unpolluted (Σ16PAHs; 19ng/g dry weight) sediment. CYP4V30 expression was much higher in worms exposed to contaminated sediments than in those exposed to unpolluted sediments at some temperatures (20 and 25°C) and exposure durations (11-fold increase at 20°C, 10-day exposure), but not at 15°C or other exposure durations (P<0.05). CYP4V30 mRNA expression was higher in the middle of the body than in the posterior (P<0.05). The variation in transcriptional response with exposure time, temperature, and body region indicates that these factors should be considered when monitoring marine sediment pollution.

Genetic Mapping with Multiple Levels of Phenotypic Information Reveals Determinants of Lymphocyte Glucocorticoid Sensitivity

Clinical response to glucocorticoids, steroid hormones widely used as pharmaceuticals, varies extensively in that many individuals (∼30%) show a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role given that glucocorticoids act largely through activation of a transcription factor, the glucocorticoid receptor. In an effort to characterize the molecular basis of variation in glucocorticoid sensitivity, we measured invitro lymphocyte glucocorticoid sensitivity and transcriptome-wide response to glucocorticoids in peripheral-blood mononuclear cells from African American healthy donors. We found that variation in lymphocyte glucocorticoid sensitivity was correlated with transcriptional response at 27 genes (false-discovery rate < 0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for lymphocyte glucocorticoid sensitivity (rs11129354, p = 4× 10(-8)); it was also associated with transcriptional response at multiple genes, including many (14/27) where transcriptional response was correlated with lymphocyte glucocorticoid sensitivity. Using allelic-imbalance assays, we show that this QTL is a glucocorticoid-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increased cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in lymphocyte glucocorticoid sensitivity reflect variation in transcriptional response, which is influenced by a glucocorticoid-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes.

Population transcriptomics of cactus host shifts in Drosophila mojavensis

In the presence of environmental change, natural selection can shape the transcriptome. Under a scenario of environmental change, genotypes that are better able to modulate gene expression to maximize fitness will tend to be favoured. Therefore, it is important to examine gene expression at the population level to distinguish random or neutral gene expression variation from the pattern produced by natural selection. This study investigates the natural variation in transcriptional response to a cactus host shift utilizing the mainland Sonora population of Drosophila mojavensis. Drosophila mojavensis is a cactophilic species composed of four cactus host populations endemic to the deserts of North America. Overall, the change in cactus host was associated with a significant reduction in larval viability as well as the differential expression of 21% of the genome (3109 genes). Among the genes identified were a set of genes previously known to be involved in xenobiotic metabolism, as well as genes involved in cellular energy production, oxidoreductase/carbohydrate metabolism, structural components and mRNA binding. Interestingly, of the 3109 genes whose expression was affected by host use, there was a significant overrepresentation of genes that lacked an orthologous call to the D.melanogaster genome, suggesting the possibility of an accelerated rate of evolution in these genes. Of the genes with a significant cactus effect, the majority, 2264 genes, did not exhibit a significant cactus-by-line interaction. This population-level approach facilitated the identification of genes involved in past cactus host shifts.

Inter-ethnic differences in lymphocyte sensitivity to glucocorticoids reflect variation in transcriptional response

Glucocorticoids (GCs) are steroid hormones widely used as pharmaceutical interventions, which act mainly by regulating gene expression levels. A large fraction of patients (~30%), especially those of African descent, show a weak response to treatment. To interrogate the contribution of variable transcriptional response to inter-ethnic differences, we measured in vitro lymphocyte GC sensitivity (LGS) and transcriptome-wide response to GCs in peripheral blood mononuclear cells (PBMCs) from African-American and European-American healthy donors. We found that transcriptional response after 8hrs treatment was significantly correlated with variation in LGS within and between populations. We found that NFKB1, a gene previously found to predict LGS within populations, was more strongly down-regulated in European-Americans on average. NFKB1 could not completely explain population differences, however, and we found an additional 177 genes with population differences in the average log2 fold change (FDR<0.05), most of which also showed a weaker transcriptional response in African-Americans. These results suggest that inter-ethnic differences in GC sensitivity reflect variation in transcriptional response at many genes, including regulators with large effects (e.g. NFKB1) and numerous other genes with smaller effects.

Genetic Variation in Radiation-Induced Expression Phenotypes

Studies have demonstrated that natural variation in the expression level of genes at baseline is extensive, and the determinants of this variation can be mapped by a genetic-linkage approach. In this study, we used lymphoblastoid cells to explore the variation in radiation-induced transcriptional changes. We found that, among normal individuals, there is extensive variation in transcriptional response to radiation exposure. By studying monozygotic twins, we demonstrated that there is evidence of a heritable component to this variation. The postradiation variation in the expression level of several genes, including the ferredoxin reductase gene (FDXR) and the cyclin-dependent kinase inhibitor 1A gene (CDKN1A), is significantly greater (P<.001) among twin pairs than within twin pairs. The induction of FDXR by radiation showed a bimodal distribution. Our findings have important implications for understanding the genetic basis of radiation response, which has remained largely unknown due to the lack of family material needed for genetic studies. Our approach, which uses expression phenotypes in cell lines, allows us to expose cells from family members to radiation. Similar study design can be applied to dissect the genetic basis of other complex human traits.