Defective insulin secretion by pancreatic ß cells underlies the development of type 2 diabetes (T2D). High fat diet-fed mice are commonly used to study diabetes progression, but studies are usually limited to a single strain, such as C57Bl/6J. Here, we use a systems biology approach to integrate large phenotypic and islet transcriptomic data sets from six commonly used strains fed a high fat or regular chow diet to identify genes associated with glucose intolerance and insulin secretion. One of these genes is Elovl2, encoding very long chain fatty acid elongase 2. ELOVL2 is responsible for the synthesis of the polyunsaturated fatty acid, docosahexaenoic acid (DHA). We show that DHA rescues glucose-induced insulin secretion and cytosolic Ca2+ influx impaired by glucolipotoxicity, and that Elovl2 over-expression is able to restore the insulin secretion defect under these conditions. We propose that increased endogenous DHA levels resulting from Elovl2 up-regulation counteracts the insulin secretion defect associated with glucolipotoxicity. Although we focus our experimental validation on Elovl2, the comprehensive data set and integrative network model we used to identify this candidate gene represents an important novel resource to dissect the molecular aetiology of ß cell failure in murine models. Overall design: 6 mouse strains, 4 time points, 2 diets
Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for <i>Elovl2</i> in glucose-induced insulin secretion.
Specimen part, Cell line, Subject, Time
View SamplesChromatin modifying activities for construction of appropriate epigenetic landscapes by polycomb repressive complex 2 (PRC2) play an essential role in development and tumorigenesis. However, the spatiotemporal mechanisms by which PRC2 achieves diverse epigenomes for specific tissue or cellular contexts remain poorly understood. Here, we discovered that LATS2 knockout causes dysregulation of PRC2 and subsequent transcriptome changes for differentiation in both mouse and human cells. LATS2 depletion dependent dysregulation of PRC2 also effects H3K4me3 and forms negative feedback loop for maintenance of PRC2. Further analyses reveal that LATS2 on chromatin binds to EZH2 and LATS2 has ability to phosphorylate PRC2 in vitro. These LATS2 dependent H3K27me3 targets are highly induced during neurogenesis, and statistical analysis of glioblastoma multiforme reveals that LATS2-high cases show more dedifferentiated transcriptome and poor prognosis with silencing of H3K27me3 targets. These observations suggest that LATS2-mediated epigenome coordination is pivotal for development and disease, including cancer. Overall design: mRNA of LATS2 KO HeLa-S3 cells rescued by empty vector, wild-type LATS2 or kinase-dead LATS2 were subjected to deep sequencing profiling using Illumina HiSeq 2500
LATS2 Positively Regulates Polycomb Repressive Complex 2.
No sample metadata fields
View SamplesIL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases.
Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A.
Specimen part, Treatment
View SamplesTriple negative breast cancer (TNBC) is an aggressive subtype that lack targeted clinical therapies. In addition, TNBC is heterogeneous and was recently further sub-classified into seven TNBC subtypes that displayed unique gene expression patterns.
Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition.
Specimen part
View SamplesTo investigate the expression characteristic of miRNAs during the development of Down syndrome (DS) fetuses and to identify whether another miRNA gene resides in the Hsa21, we employed high-throughput Solexa sequencing technology to comprehensively characterize the miRNA expression profiles of both DS and normal fetal cord blood mononuclear cells (CBMCs). In total, 200 of 395 identified miRNAs were significantly differentially expressed (fold change > 2.0 and P-value < 0.001) and 2 of 181 candidate novel miRNAs were identified as residing within the "Down syndrome critical region" of human chromosome 21 (chr21q22.2-22.3). Additionally, 7 of 14 Hsa21-derived miRNAs genes were detected that three miRNAs (hsa-miR-802, miR-3648, miR-3687) were up-regulated more than 50% and four miRNAs (hsa-miR-99a, let-7c, miR-125b-2, miR-155) were down-regulated in the DS fetal CBMCs compared with the control. Bioinformatics analyses revealed that abnormally expressed miRNAs were major associated with the regulation of transcription, gene expression, cellular biosynthetic process, macromolecule biosynthetic process and nucleic acid metabolic process. The data obtained in our study provides a considerable insight into understanding the expression characteristic of miRNAs in the DS fetal hemopoietic system and the differentially expressed miRNAs may be involved in the hemopoietic abnormalities and the immune defects of DS fetus and newborns. Overall design: A total of 6 DS and 6 matched control fetal cord blood samples (18-22 weeks of gestation) were collected. Three DS and 3 control cord blood samples were combined to form pooled DS and control cord blood samples, respectively, for small RNA library construction and Solexa sequencing. The remaining samples were used as the validation set to confirm the miRNA differential expression patterns by qRT-PCR.
Analysis of microRNA expression profile by small RNA sequencing in Down syndrome fetuses.
Specimen part, Disease, Subject
View SamplesPsoriasis is a chronic inflammatory skin disease related to immune, whose complexity of molecular mechanisms is still not fully clear. RNA sequencing has been widely applied in various fields including biological medicine. According to the bioinformatics analysis of differential genes, biomarkers and drug targets have been discovered for the diagnosis and treatment of diseases. Besides, the pathological mechanisms of disease and functions of gene can be evaluated. In the present study, we report the application of RNA sequencing in skin tissues from psoriatic and healthy persons. By obtaining 2139 differential expressed genes (DEGs), 208 significantly differential GO terms and 44 significantly differential pathways were generated. We found that the functions of DEGs were mainly related to cell cycle, inflammatory, virus, immune response and metabolic process.The major pathways included cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, chemokine signaling pathway, cell cycle, metabolic pathways, ribosome, peroxisome, steroid biosynthesis and biosynthesis of unsaturated fatty acids. Furthermore, co-expression network was constructed to identify core genes and relations between genes. we considered genes with high values of degree and k-core difference in the co-expression network as core genes, such as IFNG, IL26, TLR3, PRKCQ, TLR4, CD274, CDK1 and IL17A. We chose CD274, an important immune checkpoint, to evaluate its regulatory mechanisms. Candidate genes related to CD274 were evaluated by the co-expression network analysis, and the relations between CD274 and candidate genes were validated in epidermal keratinocytes. Finally, IFNG and CDK1 inhibitor (indirubin) were found increasing the expression levels of CD274. In addition, indirubin was confirmed to attenuate mouse psoriasis-like skin lesion with the mechanisms related to CD274. In conclusion, this study provides us a comprehensive transcriptome analysis method on psoriasis to identify core genes and explore the important regulatory functions of genes. Overall design: Nine normal skins from healthy volunteers and 18 lesional skins from patients with psoriasis vulgaris were obtained for RNA sequencing
Indirubin attenuates mouse psoriasis-like skin lesion in a CD274-dependent manner: an achievement of RNA sequencing.
Sex, Specimen part, Subject
View SamplesTrypanosoma cruzi is an obligate intracellular protozoan parasite that causes human Chagas disease, a leading cause of heart failure in Latin America. Using Affymetrix oligonucleotide arrays we screened phenotypically diverse human cells (foreskin fibroblasts, microvascular endothelial cells and vascular smooth muscle cells) for a common transcriptional response signature to T. cruzi. A common feature was a prominent type I interferon response, indicative of a secondary response to secreted cytokines. Using transwell plates to distinguish cytokine-dependent and -independent gene expression profiles in T. cruzi-infected cells, a core cytokine-independent response was identified in fibroblasts and endothelial cells that featured metabolic and signaling pathways involved in cell proliferation, amino acid catabolism and response to wounding. Significant downregulation of genes involved in mitotic cell cycle and cell division predicted that T. cruzi infection impedes cell cycle progression in the host cell.
Cytokine-dependent and-independent gene expression changes and cell cycle block revealed in Trypanosoma cruzi-infected host cells by comparative mRNA profiling.
No sample metadata fields
View SamplesExpression profile for undifferentiated F9 Embryonal Carcinoma cell line
Identification of active transcriptional regulatory modules by the functional assay of DNA from nucleosome-free regions.
No sample metadata fields
View SamplesMicroarray analysis was performed to identify transcriptional changes that occur during mucociliary differentiation of human primary bronchial epithelial cells cultured at an air-liquid interface (ALI).
Transcriptional profiling of mucociliary differentiation in human airway epithelial cells.
No sample metadata fields
View SamplesSkin-mammary specific knockout (SSKO) of Pygo2 (K14-cre; Pygo2 flox/-) , a WNT signaling co-activator, results in defective mouse mammary gland development.
Chromatin effector Pygo2 mediates Wnt-notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells.
Specimen part
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