Transcriptional profiling identifies the lncRNA PVT1 as a novel rewgulator of the asthmatic phenotype in human airway smooth muscle

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Title: Transcriptional profiling identifies the lncRNA PVT1 as a novel rewgulator of the asthmatic phenotype in human airway smooth muscle
Authors: Austin, PM
Tsitsiou, E
Boardman, C
Jones, S
Lindsay, M
Adcock, I
Chung, KF
Perry, M
Item Type: Journal Article
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.
Issue Date: 2-Jul-2016
Date of Acceptance: 13-Jun-2016
URI: http://hdl.handle.net/10044/1/34654
DOI: https://dx.doi.org/10.1016/j.jaci.2016.06.014
ISSN: 1097-6825
Publisher: Elsevier
Start Page: 780
End Page: 789
Journal / Book Title: Journal of Allergy and Clinical Immunology
Volume: 139
Issue: 3
Copyright Statement: © 2016 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Funder's Grant Number: 083905/Z/07/Z
G1000758
G1000758
NF-SI-0515-10016
Keywords: Science & Technology
Life Sciences & Biomedicine
Allergy
Immunology
Asthma
airway smooth muscle
proliferation
IL-6
transcriptome
long noncoding RNA
PVT1
CELL LUNG-CANCER
BREAST-CANCER
INFLAMMATION
EXPRESSION
PROTEIN
AMPLIFICATION
TARGET
GENES
PROLIFERATION
ASSOCIATION
Asthma
IL-6
PVT1
airway smooth muscle
long noncoding RNA
proliferation
transcriptome
Adult
Asthma
Female
Humans
Interleukin-6
Male
Middle Aged
Myocytes, Smooth Muscle
Oligonucleotide Array Sequence Analysis
Phenotype
Proto-Oncogene Proteins c-myc
RNA, Long Noncoding
RNA, Messenger
RNA, Small Interfering
Transcription, Genetic
Transcriptome
Young Adult
Myocytes, Smooth Muscle
Humans
Asthma
Proto-Oncogene Proteins c-myc
RNA, Small Interfering
RNA, Messenger
Interleukin-6
Oligonucleotide Array Sequence Analysis
Transcription, Genetic
Phenotype
Adult
Middle Aged
Female
Male
Young Adult
Transcriptome
RNA, Long Noncoding
1107 Immunology
Allergy
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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