Functional Characterization of Diabetes-Induced long non-coding RNA Dnm3os in Macrophages
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PROVIDER: PRJNA420506 | ENA |
REPOSITORIES: ENA
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Project description:Objective: Macrophages play key roles in inflammation and diabetic vascular complications. Emerging evidence implicates long noncoding RNAs (lncRNAs) in inflammation, but their role in macrophage dysfunction associated with inflammatory diabetic complications is unclear and was therefore investigated in this study. Approach and Results: RNA-sequencing and RT-qPCR demonstrated that a lncRNA Dynamin 3 opposite strand (Dnm3os) is upregulated in bone marrow derived macrophages from type2 diabetic (T2D) db/db mice, diet-induced insulin-resistant mice and diabetic ApoE-/- mice, as well as in monocytes from T2D patients relative to controls. Diabetic conditions (High glucose and palmitic acid) induced Dnm3os in mouse macrophages and THP1 human monocytes. Promoter reporter analysis and chromatin-immunoprecipitation (ChIP) assays demonstrated that diabetic conditions induce Dnm3os via NF-kB activation. RNA-FISH and RT-qPCRs of sub-cellular fractions demonstrated nuclear localization and chromatin enrichment of Dnm3os in macrophages. Stable overexpression of Dnm3os in macrophages altered global histone modifications and upregulated inflammation and immune response genes, and phagocytosis. Conversely, siRNA mediated knockdown of Dnm3os attenuated these responses. RNA pull-down assays with macrophage nuclear lysates identified nucleolin and ILF-2 as protein binding partners of Dnm3os, which was further confirmed by RNA-IP and RNA-FISH-immunofluorescence. Furthermore, nucleolin levels were decreased in diabetic conditions, and its knockdown enhanced Dnm3os-induced inflammatory gene expression and histone H3K9-acetylation at their promoters. Conclusions: These results demonstrate novel mechanisms involving upregulation of lncRNA Dnm3os, disruption of its interaction with nucleolin, and epigenetic modifications at target genes that promote macrophage inflammatory phenotype in diabetes. The data could lead to lncRNA-based therapies for inflammatory diabetes complications.
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Project description:RNA-sequencing was performed to gain insight into the mechanism responsible for the mesenchymal-to-epithelial transition (MET) induced by loss of long non-coding RNA (lncRNA) DNM3OS in SKOV3 ovarian cancer cells. Following siRNA-mediated knockdown of DNM3OS or non-targeting control, RNA-sequencing was performed. This high-throughput data revealed knockdown of DNM3OS down-regulated the expression of genes and pathways known to induce EMT in ovarian cancer.
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Project description:Improving the early diagnosis and treatment of type 2 diabetes (T2D) can effectively control blood glucose. To investigate new long non-coding RNAs (lncRNAs) as molecular markers we used microarrays to identify differentially expressed lncRNAs and mRNAs in peripheral blood mononuclear cells from T2D patients and controls.
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Project description:To identify long non-coding RNA and mRNA expression profile in the parotid gland of mouse with type 2 diabetes, and predict the potencial role of differently expressed lncRNA in the dysfunction of diabetic PG
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Project description:Sleeve gastrectomy (SG) could improve diabetes mellitus dramatically. However, the mechanisms remain largely undetermined. With the advancement of in-depth bioinformatic analysis, non-coding RNAs especially long non-coding RNAs(lncRNAs), have been implicated in many biological processes. To explore whether lncRNAs mediate the amelioration of diabetes mellitus condition after SG, we subjected liver samples of diabetic rats after SG and shame operations for RNA sequencing. Further, interaction network between lncRNAs and mRNAs/microRNAs(miRNAs) were constructed to infer the function of lncRNAs in diabetic remission, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Through RNA sequencing, we identified more than 9000 lncRNAs with a dramatically differentially expressed profile of 147 lncRNAs. Some of these specific lncRNAs were only expressed in diabetic rats after SG, which may be promising biological markers of diabetic remission and SG prognosis. Through co-analysis between lncRNAs and mRNAs, 20 potential target genes of lncRNAs were screened out. Further bioinformatic analysis indicated the differentially expressed lncRNAs harbored various miRNAs binding sites and three representative lncRNA-miRNA networks of lnc50 and lnc136 were constructed. The KEGG analysis revealed that differential expressed lncRNAs were mainly related to mitogen-activated protein kinase (MAPK) pathway. These results demonstrated that SG dramatically altered expression profile of lncRNAs on diabetes mellitus, and altered lncRNAs expression may contribute to the improvement on diabetic remission through MAPK pathway by interaction with mRNA/miRNA. Our findings provide valuable resources for molecular mechanism of diabetic remission after SG and is benefit for development of lncRNAs-based diagnostic and therapeutic interventions of diabetes mellitus.
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Project description:Macrophage dysfunction and polarization plays key role in chronic inflammation associated with diabetes and its complications. However, the effect of diabetes on macrophage transcriptome including long non-coding RNAs is not known. Here, we analyzed global changes in transcriptome of bone marrow macrophages isolated from type 2 diabetic db/db mice and control littermates db/+ mice using high throughput RNA-seq technique. Data analysis showed that expression of genes relevant to fibrosis, cell adhesion and inflammation were altered in diabetic db/db mice relative to control db/+ mice. Furthermore, expression of several known and novel long non coding RNAs and nearby genes was altered in db/db mice. Gene ontology and IPA showed activation of signaling netwroks relevant to fibrosis, cell adhesion and inflammatory pathways . This study for the first time demonstrated that diabetes profoundly affects macrophage transcriptome including expression of long non coding RNAs and altered the levels of genes relevant to diabetes complications. Bone marrow macrophages were isolated from 12 weeks old type 2 diabetic male db/db mice and control littermates db/+ mice. These were differentiated in culture for 7-8 days in the presence of 10 ng/ml of MCSF-1 (BMMC) or 20 ng/ml of GM-CSF (BMGM). Then RNA was extracted and used for RNA-seq.
2014-09-15 | E-GEOD-54154 | biostudies-arrayexpress
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Project description:Blocking the action of the PD-1 protein in lymphocytes results in their activation leading to an effective immune response in cancers and in experimental viral infections. But such immunotherapy in clinical cases results in immune adverse effects among them the development of autoimmune diabetes. In the diabetes susceptible NOD mice, blockade of the PD-L1/PD-1 pathway during the pre-diabetic stage results in severe and acute diabetes. Single-cell RNA sequencing and flow cytometry analysis of islets following blockade of the PD-L1/PD-1 pathway identified a cascade of cellular interactions involving resident macrophages and diabetogenic T cells. Such reactions led to the recruitment of monocyte derived macrophages that caused diabetes. Elimination of the monocyte derived macrophages resulted in protection. The cytocidal activity was highly dependent on IFNγ signaling and the downstream release of nitric oxide by the monocyte derived macrophages. The activation of macrophages required both the participation of CD4 and CD8 T cells. Our studies call attention to macrophages as the major effector cell following blockade of PD-1. Targeting the monocyte-derived macrophage provides a new option to prevent and treat immune checkpoint blockade induced diabetes and perhaps other immune adverse reactions.
2020-11-12 | GSE150178 | GEO
Project description:Interventions: Case series:No
Primary outcome(s): long non-coding Ribonucleic Acid
Study Design: Sequential
| 2725570 | ecrin-mdr-crc
Project description:Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1 -/- and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1 -/- mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1 -/- mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (-59%; p < 0.05). Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes.
2017-04-07 | GSE64104 | GEO