Comparison of NAT-lncRNA knockout effect by next-generation sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE200816 | GEO | 2022/06/30
REPOSITORIES: GEO
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Project description:Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia (HSP), including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of HSP. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.
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Project description:Background: Preeclampsia (PE) is a multi-systemic maternal syndrome with substantial maternal and fetal morbidity and mortality. Currently, there is no clinically viable non-invasive biomarker assay for early detection, thus limiting the effective prevention and therapeutic strategies for PE. Methods: We conducted a discovery-training-validation three-phase retrospective and prospective study with cross-platform and multicenter cohorts. The initial biomarkers were discovered and verified in tissue specimens by small RNA sequencing and qRT-PCR. A miRNA signature (miR2PE-score) was developed using the Firth’s bias-reduced logistic regression analysis, and subsequently validated in two independent multinational retrospective cohorts and two prospective plasma cohorts. Results: We initially identified five PE-associated differentially expressed miRNAs from miRNA sequencing data and subsequently validated two miRNAs (miR-196b-5p and miR-584-5p) as robust biomarkers by association analysis with clinical characteristics and qRT-PCR in tissue specimens in the discovery phase. Using the Firth’s bias-reduced logistic regression analysis, we developed the miR2PE-score for the early detection of PE. The miR2PE-score showed a high diagnostic performance with an area under the receiver operating characteristic curve (AUROC) of 0.920, 0.848, 0.864 and 0.812 in training, internal and two external validation cross-platform and multicenter cohorts, respectively. Finally, we demonstrated the non-invasive diagnostic performance of the miR2PE-score in two prospective plasma cohorts with AUROC of 0.933 and 0.787. Furthermore, the miR2PE-score revealed superior performance in non-invasive diagnosis compared with previously published miRNA biomarkers. Conclusions: We developed and validated a novel and robust blood-based miRNA signature, which may serve as a promising clinically applicable non-invasive tool for the early detection of PE.
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2018-11-21 | GSE122751 | GEO
Project description:Single cell suspensions of total thymocytes were obtained from Pten enhancer (PE) wild-type or knockout mice. This single-cell suspension was enriched in CD4-CD3- immature thymocyte progenitor cells. CD4-CD3- enriched thymocytes were then mixed 1:1 with single-cell suspensions from total unenriched thymocytes and subsequntly loaded in a 10x Chromium instrument for single-cell RNAseq analyses. Our results revealed Pten levels are signifcantly decreased in CD4-CD8- double negative (DN) thymocytes, CD8+ intermediate single positive (ISP) thymocytes and CD4+CD8+ double positive (DP) thymocytes in PE knockout mice, compared to PE wild-type mice.
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Project description:We have developed a monoclonal antibody (mAb) C7 that reacts with Als3p and enolase present in Candida albicans cell wall and exerts three anti-Candida activities: candidacidal activity and inhibition of both adhesion and filamentation. To investigate the mode of action of mAb C7 on fungal viability, we examined changes in the genome-wide gene expression profile of C. albicans grown in presence of a subinhibitory concentration of mAb C7 (12.5 µg/ml) by using microarrays. A total of 49 genes were found to be differentially expressed upon treatment with mAb C7. Of these, 28 were found to be up-regulated and 21 down-regulated. The categories of up-regulated genes with the largest number of variations were those involved in iron uptake or related to iron homeostasis (42.86%), while the energy-related group accounted for 38.10% of the down-regulated genes (8/21). Results were validated by real Time PCR. Since these effects resembled those found under iron-limited conditions, the activity of mAb C7 on C. albicans mutants with deletions in key genes implicated in the three iron acquisition systems described in this yeast was also assessed. Only mutants lacking TPK1 and TPK2 genes were less sensitive to the candidacidal effect of mAb C7. FeCl3 or hemin at concentrations ≥ 7.8µM reversed the candidacidal effect of mAb C7 on C. albicans, on a concentration dependent manner. The results presented in this study provide evidence that the candidacidal effect of mAb C7 is related to the blockage of the reductive iron uptake pathway of C. albicans. A saturated culture of C. albicans grown overnight was diluted to an optical density at 600 nm of approximately 0.1 and divided in two aliquots. One of them was used untreated as control and the second one was treated with a subinhibitory concentration (12.5 µg/ml) of monoclonal antibody C7 . Both cultures were incubated for 18 h at 37ºC before harvesting cells. Antibody added and control samples were obtained each time. The experiment was repeated once. Dye-swap technique was used for hybridization and four arrays were analyzed to compare the expresion of over six thousands genes in response to antibody C7.
2010-12-11 | E-GEOD-25969 | biostudies-arrayexpress
Project description:Background: Dystrophic epidermolysis bullosa (DEB) is a skin blistering disease caused by mutations in COL7A1, which encodes type VII collagen (C7). There is no cure for DEB, but previous work has shown potential therapeutic benefit in increasing production of even partially functional C7. Genome-wide screens using CRISPR-Cas9 have enabled the identification of genes involved in cancer development, drug resistance, and other genetic diseases, suggesting that they could be used to identify novel drivers of C7 production. Methods: A keratinocyte C7 reporter cell line was created by integrating a tdTomato fluorescent marker into the last exon of the endogenous COL7A1 gene. A genome-wide CRISPR activation (CRISPRa) screen was performed with the C7_tdTomato reporter to identify genes and pathways that increase C7 expression. High tdTomato-expressing cells were sorted and sequenced to identify the single guide RNAs (sgRNAs) that became enriched relative to the starting material. Pathway analysis was performed on the corresponding genes to identify regulators and pathways that influence C7 expression. A targeted drug screen was performed in three different keratinocyte cell lines based on the CRISPRa screen results, and C7 upregulation was evaluated. Results: The C7_tdTomato cell line was validated as an effective reporter cell line for detection of C7 upregulation. The CRISPRa screen identified two genes, DENND4B and TYROBP as top hits based on enrichment in the high fluorescence population and representation with multiple sgRNAs. Pathway analysis of the CRISPRa screen showed enrichment of toll-like receptor and interferon-related upstream regulators and functions related to calcium uptake and immune signaling. Several compounds in the targeted drug screen increased C7 expression in at least one keratinocyte line, but only kaempferol, a plant flavonoid, significantly increased C7 mRNA and protein in a DEB patient line. Conclusions: The novel C7_tdTomato reporter cell line can be used to screen compounds for increased C7 expression. The CRISPRa screen combined with a fluorescent reporter cell line can be used to reveal mechanistic regulators of gene expression and therapeutic targets for rare genetic diseases. Kaempferol has shown promising results in increasing C7 production and should be further evaluated as a potential therapeutic for DEB patients.
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