The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-β and Pulmonary Fibrosis

Savary, Grégoire; Dewaeles, Edmone; Diazzi, Serena; Buscot, Matthieu; Nottet, Nicolas; Fassy, Julien; Courcot, Elisabeth; Henaoui, Imène-Sarah; Lemaire, Julie; Martis, N.; Hauwaert, Cynthia Van der; Pons, Nicolas; Magnone, Virginie; Leroy, Sylvie; Hofman, Véronique; Plantier, Laurent; Lebrigand, Kévin; Paquet, Agnès; Cardenas, Christian L. Lino; Vassaux, Georges; Hofman, Paul; Günther, Andreas; Crestani, Bruno; Wallaert, B.; Rezzonico, Roger; Brousseau, Thierry; Guilhot, François; Bellusci, Savério; Perrais, Michaël; Broly, Franck; Barbry, Pascal; Marquette, Charles‐Hugo; Cauffiez, Christelle; Mari, Bernard; Pottier, Nicolas

doi:10.1164/rccm.201807-1237oc

Cited by 89 publications

(96 citation statements)

References 38 publications

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“…In recent years, dysfunction of ncRNAs has been proved to be associated with various complex human diseases, and increasing researchers paid attention to the roles of ncRNAs in IPF. Savary et al [14] identi ed long noncoding RNA (lncRNA) DNM3OS as a critical downstream effector of TGF-β during the activation of lung broblasts. Yang et al [15] showed that miR-200 family members (200a, 200b, and 200c) reversed brogenic responses in IPF via restraining epithelial-mesenchymal transition (EMT).…”

Section: Discussionmentioning

confidence: 99%

CircRNA TADA2A relieves idiopathic pulmonary fibrosis by inhibiting proliferation and activation of fibroblasts

Zhang

et al. 2020

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The excessive activation and proliferation of lung fibroblasts are responsible for the abundant deposition of extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF), while its specific mechanism is still unknown. This study focuses on the role of circRNA (circ) TADA2A in functional abnormalities of lung fibroblasts and aims to elaborate its regulatory mechanism. In the present study, circTADA2A was down-regulated in both IPF primary human lung fibroblasts and human IPF fibroblastic cell lines. Functionally, the overexpression of circTADA2A repressed the activation and proliferation of normal human fibroblastic cell line induced by several fibrogenic growth factors. Using fluorescence in situ hybridization (FISH), luciferase reporter assays, and RNA pull-down, circTADA2A was confirmed to function as sponges of miR-526b and miR-203, thus releasing the expression of Caveolin (Cav)-1 and Cav-2. The overexpression of circTADA2A suppressed lung fibroblasts activation via Cav-1 and reduced lung fibroblasts proliferation via Cav-2. In vivo experiments also confirmed that the overexpression of circTADA2A decreased fibrogenic responses induced by bleomycin in lung fibrosis mice. Collectively, circTADA2A repressed lung fibroblasts activation via miR-526b/Cav-1 and reduced lung fibroblasts proliferation via miR-203/Cav-2, thus inhibiting the excessive deposition of ECM and relieving IPF.

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Section: Discussionmentioning

confidence: 99%

CircRNA TADA2A relieves idiopathic pulmonary fibrosis by inhibiting proliferation and activation of fibroblasts

Zhang

et al. 2020

Preprint

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“…BHK21, MCF7, MDA-MB231, HeLa and DDIT4 +/+ and -/-MEF cells were obtained and cultured as previously described [50,[58][59][60][61][62]. Fluorescence imaging and Western blots were performed as previously described [63,64], respectively. Quantification of fluorescent cells were performed using the CellQuant program (available at:…”

Section: Cellsmentioning

confidence: 99%

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

Cambien

Lebrigand

Baeri

et al. 2020

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Mammary carcinoma, including triple-negative breast carcinomas (TNBC) are tumortypes for which human and canine pathologies are closely related at the molecular level.Low-passage, primary carcinoma cells from TNBC versus non-TNBC were used to compare the efficacy of an oncolytic vaccinia virus (VV). We show that non-TNBC cells are 28 times more sensitive to VV than TNBC cells in which VV replication is impaired.Single-cell RNA-seq performed on two different TNBC cell samples infected or not with VV highlighted three distinct populations: naïve cells, bystander cells, defined as cells exposed to the virus but not infected and infected cells. The transcriptome of these three populations showed striking variations in the modulation of pathways regulated by cytokines and growth factors. We hypothesized that the pool of genes expressed in the bystander populations was enriched in antiviral genes. Bio-informatic analysis suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. In addition, we demonstrate experimentally that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, out data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. This information could be used to design new generations of oncolytic poxviruses. Beyond the field of gene therapy, this study demonstrate that single-cell transcriptomics can be used to identify cellular factors influencing viral replication Cambien et al.3 Author summaryThe identification of cellular genes influencing viral replication/propagation have been studied using hypothesis-driven approaches and/or high-throughput RNA interference screens. In the present report, we propose a methodology based on single-cell transcriptomic. We have studied, in the context of oncolytic virothepary, the susc eptibility of primary, low-passage mammary carcinoma cells of canine origin from different grades to an oncolytic vaccinia virus (VV). We highlight a fault in replication of VV in cells originated from high-grade triple-negative breast carcinomas (TNBC).Single-cell RNA-seq performed on TNBC cell samples infected with VV suggested that the reduced activity of the virus was associated with a higher mesenchymal status of the cells. We also demonstrate that high expression of one gene, DDIT4, is detrimental to VV production. Considering that DDIT4 is associated with a poor prognosis in various cancers including TNBC, out data highlight DDIT4 as a candidate resistance marker for oncolytic poxvirus therapy. Beyond the field of cancer gene therapy, we demonstrate here that single-cell transcriptomics increases the arsenal of tools available to identify cellular factors influencing viral replication.Cambien et al.

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“…Nous avons montré son rôle clé dans la voie de signalisation du TGF-β, ainsi que son expression spécifique dans les myofibroblastes pulmonaires à l'aide d'un modèle murin de fibrose pulmonaire induite par la bléomycine. Sa surexpression exclusivement dans les myofibroblastes pulmonaires de patients atteints de FPI a ensuite été confirmée [10]. DNM3OS est un transcrit polycistronique précurseur de trois miARN matures : miR-199a-5p, préalablement caractérisé par l'équipe [9], ainsi que miR- sance essentiels à la cicatrisation, HGF (hepatocyte growth factor) et FGF7 (fibroblast growth factor 7).…”

Section: Dnm3os Un Lncarn Profibrotique Spécifiquement Exprimé Dans unclassified

“…DNM3OS est un transcrit polycistronique précurseur de trois miARN matures : miR-199a-5p, préalablement caractérisé par l'équipe [9], ainsi que miR- sance essentiels à la cicatrisation, HGF (hepatocyte growth factor) et FGF7 (fibroblast growth factor 7). Au total, ces trois miARN agissent collectivement pour amplifier des mécanismes moléculaires centraux du processus de fibrogenèse (Figure 1) [10].…”

Section: Dnm3os Un Lncarn Profibrotique Spécifiquement Exprimé Dans unclassified

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La fonction d’un long ARN non codant décodée dans la fibrose pulmonaire idiopathique

et al. 2019

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The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-β and Pulmonary Fibrosis

Cited by 89 publications

References 38 publications

CircRNA TADA2A relieves idiopathic pulmonary fibrosis by inhibiting proliferation and activation of fibroblasts

CircRNA TADA2A relieves idiopathic pulmonary fibrosis by inhibiting proliferation and activation of fibroblasts

Identification of oncolytic vaccinia restriction factors in canine high-grade mammary tumor cells using single-cell transcriptomics

La fonction d’un long ARN non codant décodée dans la fibrose pulmonaire idiopathique

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