This study addresses long-term effects of clinically relevant regimens of radiation in human glioma stem cells. Our investigations reveal a strikingly diverse spectrum of changes in cell behavior, gene expression patterns and tumor-propagating capacities evoked by radiation in different types of glioma stem cells. Evidence is provided that degree of cellular plasticity but not the propensity to self-renew is an important factor influencing radiation-induced changes in the tumor-propagating capacity of glioma stem cells. Gene expression analyses indicate that paralell transcriptomic responses to radiation underlie similarity of clinically relevant cellular outcomes such as the ability to promote tumor growth after radiation. Our findings underscore the importance of longitudinal characterizations of molecular and cellular responses evoked by cytotoxic treatrments in glioma stem cells.
Diversity of Clinically Relevant Outcomes Resulting from Hypofractionated Radiation in Human Glioma Stem Cells Mirrors Distinct Patterns of Transcriptomic Changes.
Treatment
View SamplesWe analyzed the transcriptome of the C57BL/6J mouse hypothalamus, hippocampus, neocortex, and cerebellum to determine estrous cycle-specific changes in these four brain regions. We found almost 16,000 genes are present in one or more of the brain areas but only 210 genes, ~1.3%, are significantly changed as a result of the estrous cycle. The hippocampus has the largest number of differentially expressed genes (DEGs) (82), followed by the neocortex (76), hypothalamus (63), and cerebellum (26). Most of these DEGs (186/210) are differentially expressed in only one of the four brain regions. A key finding is the unique expression pattern of growth hormone (Gh) and prolactin (Prl). Gh and Prl are the only DEGs to be expressed during only one stage of the estrous cycle (metestrus). To gain insight into the function of the DEGs, we examined gene ontology and phenotype enrichment and found significant enrichment for genes associated with myelination, hormone stimulus, and abnormal hormone levels. Additionally, 61 of the 210 DEGs are known to change in response to estrogen in the brain. 50 genes differentially expressed as a result of the estrous cycle are related to myelin and oligodendrocytes and 12 of the 63 DEGs in the hypothalamus are oligodendrocyte- and myelin-specific genes. This transcriptomic analysis reveals that gene expression in the female mouse brain is remarkably stable during the estrous cycle and demonstrates that the genes that do fluctuate are functionally related. Overall design: Hypothalamus, hippocampus, neocortex, and cerebellum mRNA from adult female C57BL/6J (B6) mice were analyzed by RNA sequencing of 3 biological replicates for each of the 4 stages of the estrous cycle using an Illumina HiSeq 2500
The stability of the transcriptome during the estrous cycle in four regions of the mouse brain.
Sex, Age, Specimen part, Cell line, Subject
View SamplesA variety of neurological disorders, including Alzheimer's disease, Parkinson's disease, major depressive disorder, dyslexia and autism, are differentially prevalent between females and males. To better understand the possible molecular basis for the sex-biased nature of neurological disorders, we measured both mRNA and protein in the hippocampus of female and male mice at 1, 2, and 4 months of age with RNA-sequencing and mass-spectrometry respectively. Differential expression analyses identify 2699 genes that are differentially expressed between animals of different ages. 198 transcripts are differentially expressed between females and males at one or more ages. The number of transcripts that are differentially expressed between females and males is greater in adult animals than in younger animals. Additionally, we identify 69 transcripts that show complex and sex-specific patterns of temporal regulation across all ages, 8 of which are heat-shock proteins. We also find a modest correlation between levels of mRNA and protein in the mouse hippocampus (Rho = 0.53). This study adds to the substantial body of evidence for transcriptomic regulation in the hippocampus during postnatal development. Additionally, this analysis reveals sex differences in the transcriptome of the developing mouse hippocampus, and further clarifies the need to include both female and male mice in longitudinal studies involving molecular changes in the hippocampus. Overall design: Hippocampal mRNA from 1, 2, and 4 month old male and female B6 mice were analyzed by RNA sequencing of 5 biological replicates using an Illumina HiSeq 2500
Sex differences in the molecular signature of the developing mouse hippocampus.
Sex, Age, Specimen part, Cell line, Subject
View SamplesNumerous neurological disorders, including Alzheimer's disease, display a sex-biased prevalence. To identify molecular correlates of this sex bias, we investigated sex-differences in molecular pathology in the hippocampus using the 5XFAD mouse model of Alzheimer's disease during early stages of disease progression (1, 2, and 4 months of age). Overall design: Hippocampal mRNA from 1, 2, and 4 month old male and female 5XFAD mice were analyzed by RNA sequencing of 5 biological replicates using an Illumina HiSeq 2500
Sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi-omic analysis.
Sex, Age, Specimen part, Cell line, Subject
View SamplesIdentifying sex differences in gene expression within the brain is critical for determining why multiple neurological and behavioral disorders differentially affect males and females. Several are more common or severe in males (e.g., autism and schizophrenia) or females (e.g., Alzheimer’s disease and depression). We analyzed transcriptomic data from the mouse hippocampus of six inbred strains (129S1/SvImJ, A/J, C57BL/6J, DBA/1J, DBA/2J and PWD/Ph), to provide a perspective on differences between male and female gene expression. Our data show that: 1) significant gene expression differences in males versus females varies substantially across the strains, 2) 12 genes exist that are differentially expressed across the inbred strains (termed core genes), and 3) there are >2,600 significantly differentially expressed genes (DEGs) among the strains (termed non-core genes). We found that DBA/2J uniquely has a substantial majority (89%) of DEGs that are more highly expressed in females than males; 129/SvImJ is the most strongly male-biased with a majority (69%) of DEGs that are more highly expressed in males. To gain insight into the sex-biased DEGs, we examined gene ontology, pathway and phenotype enrichment and found significant enrichment in phenotypes related to abnormal nervous system morphology and physiology, among others. In addition, several pathways are enriched significantly, including Alzheimer’s disease (AD), with 32 genes implicated in AD, 8 of which are male-biased. Three of the male-biased genes have been implicated in a neuroprotective role in AD. Our transcriptomic data provide new insight into understanding the possible genetic bases for sex-specific susceptibility and severity of brain disorders. Overall design: Hippocampal mRNA from adult males and females of six inbred strains of mice were analyzed by RNA sequencing of 3 biological replicates using an Illumina HiSeq 2500
Transcriptomic analysis of the hippocampus from six inbred strains of mice suggests a basis for sex-specific susceptibility and severity of neurological disorders.
Sex, Age, Specimen part, Cell line, Subject
View SamplesThe developmental transition to motherhood requires gene expression changes that alter the brain to prepare and drive the female to perform maternal behaviors. Furthermore, it is expected that the many physiological changes accompanying pregnancy and postpartum stages will impact brain gene expression patterns. To understand how extensive these gene expression changes are, we examined the global transcriptional response broadly, by examining four different brain regions: hypothalamus, hippocampus, neocortex, and cerebellum. Further, to understand the time course of these changes we performed RNA-sequencing analyses on mRNA derived from virgin females, two pregnancy time points and three postpartum time points. We find that each brain region and time point shows a unique molecular signature, with only 49 genes differentially expressed in all four regions, across the time points. Additionally, several genes previously implicated in underlying postpartum depression change expression. This study serves as a comprehensive atlas of gene expression changes in the maternal brain in the cerebellum, hippocampus, hypothalamus, and neocortex. At each of the time points analyzed, all four brain regions show extensive changes, suggesting that pregnancy, parturition, and postpartum maternal experience substantially impacts diverse brain regions. Overall design: Libraries were prepared from three independent biological replicates, mRNA for each biological replicate was derived from a single mouse brain, with each mouse brain being used to collect all four brain regions.
An Examination of Dynamic Gene Expression Changes in the Mouse Brain During Pregnancy and the Postpartum Period.
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View SamplesPrevious data suggest that 2-cysteine peroxiredoxin, cyclophilin 20-3 and the cysteine synthase complex work as a dynamically interacting module (here named COPS-module) and are involved in stress response. In this study we performed global transcriptome analyses to investigate the responses to short-term high light in wildtype and mutants deficient in each protein of COPS-module.
The redox-sensitive module of cyclophilin 20-3, 2-cysteine peroxiredoxin and cysteine synthase integrates sulfur metabolism and oxylipin signaling in the high light acclimation response.
Specimen part
View SamplesObesity is strongly associated with the metabolic syndrome, a compilation of risk factors that predispose individuals to the development of cardiometabolic disease (CMD), i.e. cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Controlling or preventing the worldwide epidemic of metabolic syndrome requires novel interventions to address this substantial health challenge. The objective of this study was the identification of potential new targets for the simultaneous prevention and treatment of insulin resistance and atherosclerosis, conditions that underlie T2DM and CVD, respectively. Therefore, we used an unbiased bioinformatics approach to identify molecules that are upregulated in both conditions by combining data from two microarray experiments and two meta-analyses. In the microarray experiments we compared gene expression in white adipose tissue (WAT) of obese mice as well as aortae of obese and atherosclerotic mice to respective lean controls. Furthermore, we performed a meta-analysis of published microarrays investigating atherosclerotic vessels and included a published meta-analysis on T2DM into our analyses. We obtained a pool of thirty-four genes that were upregulated in 3 out of the 4 underlying databases. These included well-known as well as novel crucial molecules for treatment of T2DM and CVD. Macrophage metalloelastase 12 (MMP12) was found highly ranked in all analyses and, therefore, chosen for further validation. Analyses of visceral and subcutaneous white adipose tissue from obese compared to lean mice and humans convincingly confirmed the up-regulation of MMP12 in obesity at mRNA, protein and, of note, activity levels. In conclusion, by this unbiased approach an interesting pool of potential molecular targets or biomarkers for treatment and prevention of CMD was identified with MMP12 being confirmed on multiple levels.
Identification of matrix metalloproteinase-12 as a candidate molecule for prevention and treatment of cardiometabolic disease.
Specimen part
View SamplesThe objective was to study the transcriptomic changes in adipose tissue in the early stages of lactation, specifically in Bos Taurus, Holstein dairy cattle as a function of milk production and genetic merit.
Differential expression of genes in adipose tissue of first-lactation dairy cattle.
Specimen part
View SamplesPyrimethanil (PYR) is a world-wide used fungicide approved for use in plant protection products in Agriculture, and with some (eco)toxicological concerns.We aimed at finding molecular biomarkers in the model yeast Saccharomyces cerevisiae that may be used to predict potential cytotoxic effects of this xenobiotic while providing mechanistic clues possibly relevant for experimentally less accessible non-target eukaryotes.
Potential mechanisms underlying response to effects of the fungicide pyrimethanil from gene expression profiling in Saccharomyces cerevisiae.
Treatment
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