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Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (<i>PVT1</i>) as a novel regulator of the asthmatic phenotype in human airway smooth muscle
Philip J. Austin, Eleni Tsitsiou, Charlotte Boardman, Simon W. Jones, Mark A. Lindsay, Ian M. Adcock, Kian Fan Chung, Mark M. Perry
OAI: oai:purehost.bath.ac.uk:openaire_cris_publications/a618734c-11c7-4fda-a8b6-db0bf9d1bb7e • DOI: https://doi.org/10.1016/j.jaci.2016.06.014
Abstract
Background: The mechanism underlying non-severe and severe asthma remains
unclear although it is commonly associated with increased airway smooth muscle (ASM) mass. Long non-coding RNAs (lncRNAs) are known to be important in regulating healthy primary ASM cells whilst changed expression has been observed in CD8 T-cells from patients with severe asthma.
Methods: Primary ASM cells were isolated from healthy individuals (n=9), patients classified as having non-severe asthma (n=9) or severe asthma (n=9). ASM cells were exposed to dexamethasone and fetal calf serum (FCS). mRNA and lncRNA expression was measured by microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine for relevant biological pathways. Finally, the lncRNA; Plasmacytoma Variant Translocation (PVT1) was inhibited by transfection of primary ASM cells with siRNAs, and the effect upon ASM cell phenotype was examined.
Results: The mRNA expression profile was significantly different between patient groups following exposure to dexamethasone and FCS and these were associated with biological pathways that may be relevant to the pathogenesis of asthma including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in the expression of lncRNAs, yet only one (PVT1) is decreased in expression in the corticosteroid sensitive non-severe asthmatics, and increased in expression in the corticosteroid-insensitive severe asthmatics. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASM cells from patients with severe asthma.
Conclusions: lncRNAs are associated with the aberrant phenotype observed in ASM cells from patients with asthma. Targeting of PVT1 may be effective in reducing airway remodelling in asthma.
unclear although it is commonly associated with increased airway smooth muscle (ASM) mass. Long non-coding RNAs (lncRNAs) are known to be important in regulating healthy primary ASM cells whilst changed expression has been observed in CD8 T-cells from patients with severe asthma.
Methods: Primary ASM cells were isolated from healthy individuals (n=9), patients classified as having non-severe asthma (n=9) or severe asthma (n=9). ASM cells were exposed to dexamethasone and fetal calf serum (FCS). mRNA and lncRNA expression was measured by microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine for relevant biological pathways. Finally, the lncRNA; Plasmacytoma Variant Translocation (PVT1) was inhibited by transfection of primary ASM cells with siRNAs, and the effect upon ASM cell phenotype was examined.
Results: The mRNA expression profile was significantly different between patient groups following exposure to dexamethasone and FCS and these were associated with biological pathways that may be relevant to the pathogenesis of asthma including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in the expression of lncRNAs, yet only one (PVT1) is decreased in expression in the corticosteroid sensitive non-severe asthmatics, and increased in expression in the corticosteroid-insensitive severe asthmatics. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASM cells from patients with severe asthma.
Conclusions: lncRNAs are associated with the aberrant phenotype observed in ASM cells from patients with asthma. Targeting of PVT1 may be effective in reducing airway remodelling in asthma.