Chromosomal neighbourhoods allow identification of organ specific changes in gene expression.
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ABSTRACT:
SUBMITTER: Das Roy R
PROVIDER: S-EPMC8457456 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In plants, N-acylethanolamines (NAEs) are most abundant in desiccated seeds and their levels decline during germination and early seedling establishment. However, endogenous NAE levels rise in seedlings when ABA or environmental stress is applied, and this results in an inhibition of further seedling development. When the most abundant, polyunsaturated NAEs of linoleic acid (18:2) and linolenic acid (18:3) were exogenously applied, seedling development was affected in an organ-specific manner. NAE 18:2 primarily affected primary root elongation and NAE 18:3 primarily affected cotyledon greening and expansion and overall seedling growth. The molecular components and signaling mechanisms involved in this pathway are not well understood. In addition, the bifurcating nature of this pathway provides a unique system in which to study the spatial aspects and interaction of these lipid-specific and organ-targeted signaling pathways. Using whole transcriptome sequencing (RNA-seq) and differential expression analysis, we identified early (1-3 hr) transcriptional changes induced by the exogenous treatment of NAE 18:2 and NAE 18:3 in cotyledons, roots, and seedlings. These two treatments led to a significant enrichment in ABA-response and chitin-response genes in organs where the treatments led to changes in development. In Arabidopsis seedlings, NAE 18:2 treatment led to the repression of genes involved in cell wall biogenesis and organization in roots and seedlings. In addition, cotyledons, roots, and seedlings treated with NAE 18:3 also showed a decrease in transcripts that encode proteins involved in growth processes. NAE 18:3 also led to changes in the abundance of transcripts involved in the modulation of chlorophyll biosynthesis and catabolism in cotyledons. Overall, NAE 18:2 and NAE 18:3 treatment led to lipid-type and organ-specific gene expression changes that include overlapping and non-overlapping gene sets. These data will provide future, rich opportunities to examine the genetic pathways involved in transducing early signals into downstream physiological changes in seedling growth.
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Project description:Growing evidence supports the hypothesis that the in utero environment can have profound implications for fetal development and later life offspring health. Current theory suggests conditions experienced in utero prepare, or "programme", the fetus for its anticipated post-natal environment. The mechanisms responsible for these programming events are poorly understood but are likely to involve gene expression changes. Folate is essential for normal fetal development and inadequate maternal folate supply during pregnancy has long term adverse effects for offspring. We tested the hypothesis that folate depletion during pregnancy alters offspring programming through altered gene expression. Female C57BL/6J mice were fed diets containing 2 mg or 0.4 mg folic acid/kg for 4 weeks before mating and throughout pregnancy. At 17.5 day gestation, genome-wide gene expression was measured in male fetal livers and placentas. In the fetal liver, 989 genes were expressed differentially (555 up-regulated, 434 down-regulated) in response to maternal folate depletion, with 460 genes expressed differentially (250 up-regulated, 255 down-regulated) in the placenta. Only 25 differentially expressed genes were common between organs. Maternal folate intake during pregnancy influences fetal gene expression in a highly organ specific manner which may reflect organ-specific functions.
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Project description:In cancer genomes, changes observed during tumor progression can be difficult to separate from nonspecific accumulation of cytogenetic changes due to cancer-associated genetic instability. We studied genetic changes occurring over time in cancers presenting with a relatively simple karyotype, namely two related core-binding factor (CBF) acute myeloid leukemias (AMLs), to assess how specific chromosomal changes are selected based on tumor subtype and acquired somatic mutations. Expression profiles for DNA replication/repair genes and the mutation status of KRAS, NRAS, FLT3, and KIT were compared with the karyotypic changes at diagnosis and relapse(s) in 94 cases of inv(16)(p13.1q22)-AML and 82 cases of t(8;21)(q22;q22)-AML. The majority of both AML types demonstrated a simple aneuploid pattern of cytogenetic progression, with highly distinctive patterns of chromosome copy number changes, such as +22 and +13 exclusively in inv(16)-AML and -Y and -X in t(8;21)-AML. Selection of certain cytogenetic changes correlated with particular somatic mutations, such as +8 with RAS mutation, and absence of kinase pathway mutations in t(8;21)-AML with localized deletions at chromosome band 9q22. Alterations in transcript levels of mitotic spindle kinases such as CHEK1, AURKA, and AURKB were associated with the aneuploid progression pattern, particularly in t(8;21) cases. Despite the similarity in the initiating genetics of the two CBF AML types, highly tumor-specific patterns of limited aneuploidy are noted that persist and continue to accumulate at relapse. Thus, activation of genetic instability, possibly through mitotic spindle dysregulation, leads rapidly to the selection of advantageous single chromosome aneuploidy.
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Project description:BACKGROUND:The chemosensory system plays an important role in orchestrating sexual behaviors in mammals. Pheromones trigger sexually dimorphic behaviors and different mouse strains exhibit differential responses to pheromone stimuli. It has been speculated that differential gene expression in the sensory organs that detect pheromones may underlie sexually-dimorphic and strain-specific responses to pheromone cues. RESULTS:We have performed transcriptome analyses of the mouse vomeronasal organ, a sensory organ recognizing pheromones and interspecies cues. We find little evidence of sexual dimorphism in gene expression except for Xist, an essential gene for X-linked gene inactivation. Variations in gene expression are found mainly among strains, with genes from immune response and chemosensory receptor classes dominating the list. Differentially expressed genes are concentrated in genomic hotspots enriched in these families of genes. Some chemosensory receptors show exclusive patterns of expression in different strains. We find high levels of single nucleotide polymorphism in chemosensory receptor pseudogenes, some of which lead to functionalized receptors. Moreover, we identify a number of differentially expressed long noncoding RNA species showing strong correlation or anti-correlation with chemoreceptor genes. CONCLUSIONS:Our analyses provide little evidence supporting sexually dimorphic gene expression in the vomeronasal organ that may underlie dimorphic pheromone responses. In contrast, we find pronounced variations in the expression of immune response related genes, vomeronasal and G-protein coupled receptor genes among different mouse strains. These findings raised the possibility that diverse strains of mouse perceive pheromone cues differently and behavioral difference among strains in response to pheromone may first arise from differential detection of pheromones. On the other hand, sexually dimorphic responses to pheromones more likely originate from dimorphic neural circuits in the brain than from differential detection. Moreover, noncoding RNA may offer a potential regulatory mechanism controlling the differential expression patterns.
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Project description:The origins of multicellular physiology are tied to evolution of gene expression. Genes can shift expression as organisms evolve, but how ancestral expression influences altered descendant expression is not well understood. To examine this, we amalgamate 1,903 RNA-seq datasets from 182 research projects, including 6 organs in 21 vertebrate species. Quality control eliminates project-specific biases, and expression shifts are reconstructed using gene-family-wise phylogenetic Ornstein-Uhlenbeck models. Expression shifts following gene duplication result in more drastic changes in expression properties than shifts without gene duplication. The expression properties are tightly coupled with protein evolutionary rate, depending on whether and how gene duplication occurred. Fluxes in expression patterns among organs are nonrandom, forming modular connections that are reshaped by gene duplication. Thus, if expression shifts, ancestral expression in some organs induces a strong propensity for expression in particular organs in descendants. Regardless of whether the shifts are adaptive or not, this supports a major role for what might be termed preadaptive pathways of gene expression evolution.
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Project description:BackgroundVisceral organ metastasis is associated with poor survival outcomes in terms of metastasis free- and overall survival in breast carcinomas. Identification of a gene expression profile in tumours that selects a subpopulation of patients that is more likely to develop visceral organ metastases will help elucidate mechanisms for the development of distant metastases and could be of clinical value. With this study we aimed to determine genomic predictors that would help to distinguish breast cancer patients with more likelihood to develop visceral metastasis.MethodsGene expression profiling data of 157 primary tumours from breast cancer patients who developed distant metastases were analyzed and differentially expressed genes between the group of tumours with visceral metastasis and the those without visceral metastases were identified. Published data were used to validate our findings. Multivariate logistic regression tests were applied to further investigate the association between the gene-expression-signature and clinical variables. Survival analyses were performed by the Kaplan-Meier method.ResultsFourteen differentially expressed genes (WDR6, CDYL, ATP6V0A4, CHAD, IDUA, MYL5, PREP, RTN4IP1, BTG2, TPRG1, ABHD14A, KIF18A, S100PBP and BEND3) were identified between the group of tumours with and without visceral metastatic disease. Five of these genes (CDYL, ATP6V0A4, PREP, RTN4IP1 and KIF18A) were up-regulated and the other genes were down-regulated. This gene expression signature was validated in the training and in the independent data set (p 2.13e- 08 and p 9.68e- 06, respectively). Multivariate analyses revealed that the 14-gene-expression-signature was associated with visceral metastatic disease (p 0.001, 95% CI 1.43-4.27), independent of other clinicopathologic features. This signature has been also found to be associated with survival status of the patients (p < .001).ConclusionWe have identified an unique gene expression signature which is specific to visceral metastasis. This 14-gene-expression-signature may play a role in identifying the subgroup of patients with potential to develop visceral metastasis.
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Project description:The study of drug toxicity in human organs is complicated by their complex inter-relations and by the obvious difficulty to testing drug effects on biologically relevant material. Animal models and human cell cultures offer alternatives for systematic and large-scale profiling of drug effects on gene expression level, as typically found in the so-called toxicogenomics datasets. However, the complexity of these data, which includes variable drug doses, time points, and experimental setups, makes it difficult to choose and integrate the data, and to evaluate the appropriateness of one or another model system to study drug toxicity (of particular drugs) of particular human organs. Here, we define a protocol to integrate drug-wise rankings of gene expression changes in toxicogenomics data, which we apply to the TG-GATEs dataset, to prioritize genes for association to drug toxicity in liver or kidney. Contrast of the results with sets of known human genes associated to drug toxicity in the literature allows to compare different rank aggregation approaches for the task at hand. Collectively, ranks from multiple models point to genes not previously associated to toxicity, notably, the PCNA clamp associated factor (PCLAF), and genes regulated by the master regulator of the antioxidant response NFE2L2, such as NQO1 and SRXN1. In addition, comparing gene ranks from different models allowed us to evaluate striking differences in terms of toxicity-associated genes between human and rat hepatocytes or between rat liver and rat hepatocytes. We interpret these results to point to the different molecular functions associated to organ toxicity that are best described by each model. We conclude that the expected production of toxicogenomics panels with larger numbers of drugs and models, in combination with the ongoing increase of the experimental literature in organ toxicity, will lead to increasingly better associations of genes for organism toxicity.
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Project description:Purpose: Using RNA-seq and differential expression analysis, we examined the NAE-type and organ-specific genetic pathways involved in transducing ear;y signals into downstream physiological changes involved in Arabidopsis seedling growth. Methods: Intact seedlings and dissected cotyledon and root mRNA profiles of 3-day-old Arabidopsis seedlings treated with DMSO, 40 µM NAE 18:2 or 80 µM NAE 18:3 were generated by deep sequencing, in triplicate, using the Illumina Next-Seq 500 system. The sequence reads that passed quality filters were analyzed using STAR followed by DESeq2. qRT–PCR validation was performed using SYBR Green assays Results: Using RNA-seq and differential expression analysis, we identified early (1 h) transcriptional changes induced by the exogenous treatment of NAE 18:2 and NAE 18:3 in cotyledons, roots and intact seedlings. These two treatments led to a significant enrichment in ABA-response and chitin-response genes in organs where the treatments led to changes in development. In Arabidopsis seedlings, NAE 18:2 treatment led to the repression of genes involved in cell wall biogenesis and organization in roots and seedlings. In addition, cotyledons, roots, and seedlings treated with NAE 18:3 also showed a decrease in transcripts that encode proteins involved in growth processes. NAE 18:3 also led to changes in the abundance of transcripts involved in the modulation of chlorophyll biosynthesis and catabolism in cotyledons. Overall, NAE 18:2 and NAE 18:3 treatment led to lipid-type and organ-specific gene expression changes that include overlapping and non-overlapping gene sets. These data will provide future, rich opportunities to examine the genetic pathways involved in transducing early signals into downstream physiological changes in seedling growth. Conclusions: A detailed transcriptional analyses provided insight into the early organ-specific molecular responses to NAE 18:2 and NAE 18:3. Using this experimental and computational approach, we gained an unbiased view of the NAE 18:2- and NAE 18:3-modulated transcriptome changes that are activated and lead to downstream changes in seedling development. NAE 18:2 and NAE 18:3 induced the expression of several genes also induced by ABA or chitin treatment. The overlap with ABA-response genes corroborates previously work; however, this is the first time chitin-response genes have been identified as part of the NAE-modulation of seedling growth. Overall, the bioinformatic analyses presented here supports the hypothesis that NAE 18:2 and NAE 18:3 elicit organ-specific and signal- specific molecular changes that precede developmental changes in Arabidopsis seedlings. Further, these data provide novel insights into the genetic programs that are modulated by NAE 18:2 and NAE 18:3 at the organ-specific level in Arabidopsis seedlings, and will facilitate future studies of the corresponding signaling networks.
2020-06-30 | GSE134271 | GEO
Project description:The brain, spinal cord, and retina are supplied by capillaries that do not permit free diffusion of molecules between serum and parenchyma, a property that defines the blood-brain and blood-retina barriers. Exceptions to this pattern are found in circumventricular organs (CVOs), small midline brain structures that are supplied by high permeability capillaries. In the eye and brain, high permeability capillaries are also present in the choriocapillaris, which supplies the retinal pigment epithelium and photoreceptors, and the ciliary body and choroid plexus, the sources of aqueous humor and cerebrospinal fluid, respectively. We show here that (1) endothelial cells in these high permeability vascular systems have very low beta-catenin signaling compared to barrier-competent endothelial cells, and (2) elevating beta-catenin signaling leads to a partial conversion of permeable endothelial cells to a barrier-type state. In one CVO, the area postrema, high permeability is maintained, in part, by local production of Wnt inhibitory factor-1.
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