A multi-omics analysis of the regulatory changes induced by miR-223 in a monocyte/macrophage cell line
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE121077 | GEO | 2018/10/11
REPOSITORIES: GEO
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Project description:We used a multi-omics approach combining transcriptomics, proteomics and metabolomics to study the impact of over-expression and inhibition of the microRNA miR-223, a pleiotropic regulator of metabolic-related disease, in the RAW monocyte-macrophage cell line. We analyzed the levels of proteins, mRNAs, and metabolites in order to identify genes involved in miR-223 regulation, to determine candidate disease biomarkers and potential therapeutic targets. We observed that both up- and down-regulation of miR-223 induced profound changes in the mRNA, protein and metabolite profiles in RAW cells. Microarray-based transcriptomics evidenced a change in 120 genes that were linked predominantly to histone acetylation, bone remodeling and RNA regulation. In addition, 30 out the 120 genes encoded long noncoding RNAs. The nanoLC-MS/MS revealed that 52 proteins were significantly altered when comparing scramble, pre- and anti-miR-223 treatments. Sixteen out of the mRNAs coding these proteins genes are predicted to have binding sites for miR-223. CARM-1, Ube2g2, Cactin and Ndufaf4 were confirmed to be miR-223 targets by western blotting. Analyses using Gene Ontology annotations evidenced association with cell death, splicing and stability of mRNAs, bone remodeling and cell metabolism. miR-223 alteration changed the expression of CARM-1, Ube2g2, Cactin and Ndufaf4 during osteoclastogenesis and macrophage, indicating that these genes are potential biomarkers of these processes. The most important discriminant metabolites found in the metabolomics study were found to be hydrophilic amino acids, carboxylic acids linked to metabolism and pyrimidine nucleotides, indicating that changes in miR-223 expression alter the metabolic profile of cells, and may affect their apoptotic and proliferative state.
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Project description:miR-223 is step-wise increasingly up-regulated in the normal esophagus - Barrett's esophagus -esophageal adenocarcinoma carcinoma sequence. In this study, we aimed to determine the function of miR-223 in esophageal adenocarcinoma carcinogenesis. miR-223 was transfected in OE33 cells using 10nM pre-miR hsa-miR-223 miRNA precursor (Ambion, Life Technologies, Grand Island, NY) and lipofectamin 2000 (OE33_223_1 and OE33_223_2). Mock control OE33 cells were transfected with a negative control pre-miR miRNA (OE33_NEG_1 and OE33_NEG_2). HumanHT-12 v4 Expression BeadChip arrays (Illumina, San Diego, CA) were used for microarray hybridizations to examine the global gene expression of two biological replicated experiments (four samples in total). The array targets more than 25,000 annotated genes with 47,323 unique probes derived from the National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) Release 38 and UniGene (Build 199) databases.
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Project description:A multi-omics analysis of the regulatory changes induced by miR-223 in a monocyte/macrophage cell line
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Project description:MicroRNA-223, a principal myeloid-specific anti-inflammatory microRNA, is dysregulated in numerous inflammatory conditions and cancers. We found that miR-223 deficient zebrafish displayed augmented neutrophilic inflammation, which was due primarily to elevated activation of the canonical NF-B pathway. To our surprise, the NF-B over-activation was restricted to the basal epithelial cells, a squamous layer permeable to oxygen and chemicals. MiR-223 was expressed in epithelial cells and directly down-regulated multiple components in the NF-B signaling pathway in zebrafish and human. Both phagocytic and epithelial miR-223 suppressed neutrophil wound response and NF-B activation in the basal epithelial cells. Together, our data provide the mechanism of the multifaceted role of miR-223 and highlight the previously overlooked relevance of epithelial cells in miR-223 related diseases.
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Project description:Acute lung injury (ALI) is characterized by acute respiratory failure in the setting of non-cardiogenic pulmonary edema, causing acute respiratory distress syndrome (ARDS) in patients and contributes significantly to mortality of critically illness. The main goal of our study is to elucidate the role of miRNAs in neutrophil-epithelial communication during pulmonary inflammation and thereby identifying novel targets for therapy of acute lung injury (ALI). In our studies we identified a miR-223-dependent neutrophil-epithelial crosstalk during ALI. Activated neutrophils (PMN) and pulmonary epithelial cells come into a close spatial relationship during ALI. And, since previous studies had indicated the possibility that inflammatory cell-dependent release of miRNA-containing microvesicles could function as a means of exchanging genetic information from a donor to a target cell, we assessed PMN-elicited alterations of pulmonary epithelial miRNA expression in an experimental co-culture setup. This approach provided a selective and extremely robust readout: While other miRNAs were not or only moderately altered in their expression, pulmonary-epithelial-expressed miR-223 was significantly induced after 4 or 6h of co-incubation. Additional in vitro and in vivo studies clearly demonstrate that this increase of epithelial miR-223 is not due to miR-223 transcriptional induction, but instead PMN-dependent and caused by shuttling miR-223 from PMN into pulmonary epithelial cells. To address the functional role of miR-223-dependent neutrophil-epithelial crosstalk during ALI, we exposed mice to ventilator-induced ALI and observed robust induction of pulmonary miR-223 during ALI, while increases of miR-223 were completely abolished after antibody-depletion of PMN. Moreover, studies of alveolar epithelial cells isolated from mice with ALI showed robust increases of miR-223, indicating that miR-223 is shuttled from PMN towards alveolar epithelia during ALI in vivo. Functional studies revealed that gene-targeted mice for miR-223 experience a more severe phenotype during ALI as compared to controls, while their phenotype could be resuscitated by nanoparticle-mediated overexpression of miR-223 in the lungs. In summary, these studies reveal a novel role of miR-223-dependent neutrophil-epithelial crosstalk representing an anti-inflammatory pathway that can be targeted for ALI treatment.
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Project description:Exposure of pregnant F0 mouse dams to the obesogen tributyltin (TBT) predisposes unexposed male descendants to obesity and diverts mesenchymal stem cells (MSCs) toward the adipocytic lineage. TBT also promotes adipogenic commitment and differentiation of MSCs, in vitro. We sought to identify TBT-induced factors predisposing MSCs toward the adipocytic fate. We exposed mouse MSCs to TBT, the PPARγ-selective agonist rosiglitazone or the RXR-selective agonist LG-100268 and determined their transcriptomal profiles to determine candidate microRNAs (miR) regulating adipogenic commitment and differentiation. Of the top 10 candidate microRNAs predicted by Ingenuity Pathway Analysis, miR-21, miR-33 and miR-223 were expressed to regulate genes differentially expressed in adipogenesis. After exposing to 50 nM TBT for 24 hours, miR-223 levels of MSCs were increased and expression of its target genes ZEB1, NFIB, and FOXP1 decreased. Both ROSI and TBT increased miR-223 levels, and this induction was inhibited by PPARγ antagonists (T0070907) but not RXR antagonists (HX531, UVI3003), placing miR-223 downstream of PPARγ. Chromatin immunoprecipitation confirmed TBT-induced binding of PPARγ to regulatory elements in the miR-223 promoter. miR-223 levels were elevated in ancestral TBT exposed F2 and F3 male adipose tissues and further increased when animals were fed with a high fat diet. TBT induced miR-223 expression and adipogenesis in MSCs through the PPARγ pathway and promoted elevated miR-223 expression in white adipose tissue of F2 and F3 male descendants of F0 treated dams. This shows that transgenerationally increased expression of miR-223 plays an important role in the transmission of the obese phenotype after TBT exposure.
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