MiR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis
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ABSTRACT:
PROVIDER: PRJNA868177 | ENA |
REPOSITORIES: ENA
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Project description:MicroRNAs (miRNAs) constitute fine tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA), however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. We have shown in the past that the expression of the miR-221/222 cluster is upregulated in RA SFs. Here, we demonstrate that miR-221/222 activation is downstream of major inflammatory cytokines, such as TNF and IL-1β, which promote miR-221/222 expression independently. miR-221/222 expression in SFs from the huTNFtg mouse model of arthritis correlates with disease progression. Targeted transgenic overexpression of miR-221/222 in SFs of the huTNFtg mouse model led to further expansion of synovial fibroblasts and disease exacerbation. miR-221/222 overexpression altered the transcriptional profile of SFs igniting pathways involved in cell cycle progression and ECM regulation. Validated targets of miR-221/222 included p27 and p57 cell cycle inhibitors, as well as Smarca1 (a chromatin remodeling component). In contrast, complete genetic ablation of miR-221/222 in arthritic mice led to decreased proliferation of fibroblasts, reduced synovial expansion and attenuated disease. scATAC-seq data analysis revealed increased miR-221/222 gene activity in the pathogenic and activated clusters of the intermediate and lining compartment. Taken together, our results establish an SF-specific pathogenic role of the miR-221/222 cluster in arthritis and suggest that its therapeutic targeting in specific subpopulations should inform the design of novel fibroblast-targeted therapies for human disease.
2022-12-16 | GSE210887 | GEO
Project description:Full title: Expression data from antisense miRNA-221/222 (si221/222) and control inhibitor (GFP) treated fulvestrant-resistant breast cancer cells The expression of miR-221/222 were found to be upregulated in fulvestrant resistant breast cancer cells MCF7-FR compared to its drug-sensitive counterpart MCF7. To investigate the role of miR-221/222 in acquired resistance to fulvestrant, we lowered the level of miR-221/222 in MCF7-FR cells using miRNA inhibitors (antagomirs), and compared gene expression profiles before and after treatment.
2011-01-29 | GSE19777 | GEO
Project description:Analysis of gene expression of MCF10A to identify the targets of miR-221 and miR-222 Keywords: MCF10, miR-221, miR-222
2011-06-14 | GSE29327 | GEO
Project description:Analysis of gene expression of MCF10A to identify the targets of miR-221 and miR-222 Keywords: MCF10, miR-221, miR-222 RNA profiles of human MCF10A cell line
2011-06-14 | E-GEOD-29327 | biostudies-arrayexpress
Project description:Full title: Expression data from antisense miRNA-221/222 (si221/222) and control inhibitor (GFP) treated fulvestrant-resistant breast cancer cells The expression of miR-221/222 were found to be upregulated in fulvestrant resistant breast cancer cells MCF7-FR compared to its drug-sensitive counterpart MCF7. To investigate the role of miR-221/222 in acquired resistance to fulvestrant, we lowered the level of miR-221/222 in MCF7-FR cells using miRNA inhibitors (antagomirs), and compared gene expression profiles before and after treatment. Fulvestrant-resistant breast cancer cells MCF7-FR (originated from drug-sentitive breast cancer model cell line MCF7) were transient-transfected by antigomirs targeting miR221 or miR222 (i.e. si221, si222). All three cell lines, MCF7-FR, siR221, siRNA222 were subjected to gene expression profiling.
2011-01-29 | E-GEOD-19777 | biostudies-arrayexpress
Project description:To evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines as well as one immortalized normal human bronchial epithelial cell line. Two cell lines, H3255 and H1299 with no replicates were studied. Cells were transfected with miR-221, miR-222, or miR control. Microarray analysis was done to identify genes differentially expressed in lung cancer cells after the transfection of miR-221 or miR-222.
2015-05-22 | E-GEOD-57676 | biostudies-arrayexpress
Project description:To evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines as well as one immortalized normal human bronchial epithelial cell line.
2015-05-22 | GSE57676 | GEO
Project description:Objectives: This study was undertaken to understand the mechanistic basis of response to anti-TNF therapies and determine if transcriptomic changes in the synovium are reflected in peripheral protein markers. Methods: Synovial tissue from 46 RA patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among EULAR good, moderate and non-responders. Serum proteins encoded by synovial genes differentially expressed between EULAR response groups were measured in the same patients. Results: The gene signatures were able to predict good responder patients and pathway analysis identified elevations in immune pathways including chemokine signaling, Th1 and Th2 cell differentiation, and Toll-like receptor signaling uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid and fibroblast cell populations were elevated in good responders relative to non-responders, consistent with the increased inflammatory pathways. Cell signatures which decreased following anti-TNF treatment were predominately associated with lymphocytes and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment and only in good responders, several peripheral inflammatory proteins decreased consistent with corresponding synovial gene changes. Conclusions: Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF may assist in development of predictive markers of patient response and earlier treatment options.
2022-06-06 | GSE198520 | GEO
Project description:Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation. Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation.
2021-08-24 | GSE182498 | GEO
Project description:compared miR-221/222-3p deficient (KO) and WT (Flox) activated B cell mRNAseq and Ago2-HITSCLIP to determine mRNA targets of this miRNA cluster
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