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Transcriptional Profiling Identifies the Lncrna PVT1 As a Novel Regulator of the Asthmatic Phenotype in Human Airway Smooth Muscle

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Transcriptional Profiling Identifies the Lncrna PVT1 As a Novel Regulator of the Asthmatic Phenotype in Human Airway Smooth Muscle Accepted Manuscript Transcriptional profiling identifies the lncRNA PVT1 as a novel regulator of the asthmatic phenotype in human airway smooth muscle Philip J. Austin, MSc, Eleni Tsitsiou, PhD, Charlotte Boardman, MD, Simon W. Jones, PhD, Mark A. Lindsay, PhD, Ian M. Adcock, PhD, Kian Fan Chung, MD PhD, Mark M. Perry, PhD PII: S0091-6749(16)30571-1 DOI: 10.1016/j.jaci.2016.06.014 Reference: YMAI 12203 To appear in: Journal of Allergy and Clinical Immunology Received Date: 5 April 2016 Revised Date: 24 May 2016 Accepted Date: 13 June 2016 Please cite this article as: Austin PJ, Tsitsiou E, Boardman C, Jones SW, Lindsay MA, Adcock IM, Chung KF, Perry MM, Transcriptional profiling identifies the lncRNA PVT1 as a novel regulator of the asthmatic phenotype in human airway smooth muscle, Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.06.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT 1 Transcriptional profiling identifies the lncRNA PVT1 as a novel 2 regulator of the asthmatic phenotype in human airway smooth muscle 3 4 Philip J. Austin MSc 1, Eleni Tsitsiou PhD 2, Charlotte Boardman MD 1, Simon W. 5 Jones PhD 3, Mark A. Lindsay PhD 1,2,4, Ian M. Adcock PhD 1, Kian Fan Chung MD 6 PhD 1 and Mark M. Perry PhD 5* 7 8 Author Affiliations: 1Airways Disease, National Heart and Lung Institute, Imperial 9 College, London & Royal Brompton NIHR Biomedical Research Unit, London SW3 10 6LY, United Kingdom, 2Respiratory Research Group, University Hospital of South 11 Manchester, University of Manchester, Southmoor Road, Manchester M23 9LY, 12 United Kingdom, 3Institute of Inflammation and Ageing, University of Birmingham, 4 13 Birmingham, B15 2TT, Department of PharmacyMANUSCRIPT and Pharmacology, University of 14 Bath, Claverton Down, Bath, BA2 7AY, United Kingdom, 5The Dubowitz 15 Neuromuscular Centre, Molecular Neurosciences Section, Developmental 16 Neurosciences Programme, UCL Institute of Child Health, 30 Guildford Street, 17 London, WC1N 1EH 18 19 *Corresponding Author: 20 Dr Mark M Perry 21 The DubowitzACCEPTED Neuromuscular Centre, 22 Molecular Neurosciences Section, 23 Developmental Neurosciences Programme, 24 UCL Institute of Child Health 25 30 Guildford Street ACCEPTED MANUSCRIPT 26 London 27 WC1N 1EH 28 Tel: 0207 905 2136 29 Fax: 0207 905 2832 30 Email: [email protected] 31 32 Funding bodies 33 This work was supported by a fellowship from Imperial College London (JRF), grants 34 from Asthma UK (08/041) and The Wellcome Trust (085935) (KFC). This project was 35 supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal 36 Brompton and Harefield NHS Foundation Trust and Imperial College London. The 37 views expressed in this publication are those of the authors(s) and not necessarily 38 those of the NHS, The National Institute for Health Research or the Department of 39 Health. KFC is a Senior Investigator of NIHR,MANUSCRIPT UK. MMP was an Imperial College 40 Research Fellow. MMP, IMA and KFC are members of Interuniversity Attraction 41 Poles Program-Belgian State-Belgian Science Policy- project P7/30. 42 43 Contributors 44 MP, ML, IA and KFC were responsible for preparation of the manuscript; MP, PA 45 and CB conducted in-vitro experiments; ET conducted microarrays; MP, SJ and ML 46 analysed microarraysACCEPTED and undertook statistical analysis. ACCEPTED MANUSCRIPT 47 Abstract 48 Background: The mechanism underlying non-severe and severe asthma remains 49 unclear although it is commonly associated with increased airway smooth muscle 50 (ASM) mass. Long non-coding RNAs (lncRNAs) are known to be important in 51 regulating healthy primary ASM cells whilst changed expression has been observed in 52 CD8 T-cells from patients with severe asthma. 53 Methods: Primary ASM cells were isolated from healthy individuals ( n=9), patients 54 classified as having non-severe asthma (n=9) or severe asthma (n=9). ASM cells were 55 exposed to dexamethasone and fetal calf serum (FCS). mRNA and lncRNA expression 56 was measured by microarray and quantitative real-time PCR. Bioinformatic analysis 57 was used to examine for relevant biological pathways. Finally, the lncRNA; 58 Plasmacytoma Variant Translocation (PVT1 ) was inhibited by transfection of primary 59 ASM cells with siRNAs, and the effect upon ASM cell phenotype was examined. 60 Results: The mRNA expression profile wasMANUSCRIPT significantly different between patient 61 groups following exposure to dexamethasone and FCS and these were associated with 62 biological pathways that may be relevant to the pathogenesis of asthma including 63 cellular proliferation and pathways associated with glucocorticoid activity. We also 64 observed a significant change in the expression of lncRNAs, yet only one ( PVT1 ) is 65 decreased in expression in the corticosteroid sensitive non-severe asthmatics, and 66 increased in expression in the corticosteroid-insensitive severe asthmatics. Subsequent 67 targeting studiesACCEPTED demonstrated the importance of this lncRNA in controlling both 68 proliferation and IL-6 release in ASM cells from patients with severe asthma. 69 Conclusions: lncRNAs are associated with the aberrant phenotype observed in ASM 70 cells from patients with asthma. Targeting of PVT1 may be effective in reducing 71 airway remodelling in asthma. ACCEPTED MANUSCRIPT 72 73 Capsule Summary 74 Our data suggest that lncRNA patterns are differentially dysregulated in non-severe 75 asthmatic patients and severe asthmatic patients, and that targeting the lncRNA; PVT1 76 may provide a treatment for asthma. 77 78 Key Words: Asthma, Airway Smooth Muscle, Proliferation, IL-6, Transcriptome, 79 Long noncoding RNA, PVT1 80 81 Abbreviations used: 82 ASMC: Airway Smooth Muscle Cell 83 CS: Corticosteroids 84 lncRNA: Long non-coding RNA 85 miRNA: microRNA MANUSCRIPT 86 PVT1: Plasmacytoma Variant Translocation 87 88 Key Messages: 89 • Severe asthma is a worldwide health issue that is mostly unresponsive to 90 existing therapy. 91 • lncRNAs are differentially expressed between ASM cells from patients with 92 non-severeACCEPTED and severe asthma. 93 • Targeting of the lncRNA; PVT1 , can reduce the increased cellular proliferation 94 and IL-6 release from ASM cells in severe asthma. ACCEPTED MANUSCRIPT 95 Introduction 96 Asthma is characterized by airflow obstruction and chronic airway inflammation and 97 remodeling (1) . Airway smooth muscle (ASM) hyperplasia and hypertrophy leads to 98 increased airway wall thickening and airway narrowing, contributing to the airway 99 obstruction and inflammation. Epigenetic mechanisms are key regulators of ASM 100 function (2) . We have reported that the aberrant phenotype of ASM cells (ASMCs) from 101 patients with asthma is under the negative regulation of cyclin inhibitors, p21 WAF1 & 102 p27 kip1 , which are controlled by microRNA-221 (3) . Furthermore, by utilizing a 103 transcriptiomic-based approach, we identified potential miRNA targets and pathways 104 in activated human ASMCs and observed changes in expression of lncRNAs, 105 including natural antisense, pseudogenes, intronic lncRNAs, and intergenic 106 lncRNAs (4) . 107 108 Having reported the results of the healthy, (orMANUSCRIPT ‘non-asthmatic’) ASMCs in 2014 (4) , we 109 now report upon the asthmatic ASMCs that were studied at the same time. 110 Specifically, we report upon the differential expression of mRNAs and lncRNAs in 111 ASMCs isolated from non-severe and severe asthmatic individuals, and treated with 112 dexamethasone before subsequent activation with the growth medium, fetal calf serum 113 (FCS). We have then focused upon the only lncRNA found to be decreased in 114 expression in the corticosteroid sensitive non-severe asthmatics, and increased in 115 expression inACCEPTED the corticosteroid-insensitive severe asthmatics; plasmacytoma variant 116 translocation (PVT)1 , and performed targeting studies to examine its role in a 117 corticosteroid insensitivity model in these cells induced by the combination of TGF-β 118 and FCS. 119 ACCEPTED MANUSCRIPT 120 Methods 121 Full methodology is available in the Supplemental data file . 122 123 Subject selection and ASMC culture 124 Primary ASMCs from healthy individuals, non-severe asthmatics and severe 125 asthmatics were treated as described previously (4-7) . Patient characteristics are in Table 126 1. 127 128 RNA extraction 129 RNA was extracted using the mir Vana™miRNA isolation kit, as previously 130 described (4-8) . 131 132 Microarray Analysis 133 LncRNA and mRNA expression was determinedMANUSCRIPT using the Agilent SurePrint G3 134 Human GE microarrays following the manufacturer’s instructions, and as previously 135 described (4) . Total RNA samples (50 ng) used in lncRNA and mRNA microarrays 136 were initially labelled with Spike-In control A (for Cyanine 3-CTP) or B (for Cyanine 137 5-CTP). Labelled samples were then used for cDNA synthesis using the cDNA Master 138 Mix (Agilent) and were incubated for 2 h at 40°C followed by 15 min at 70°C to 139 inactivate the Affinity-Script enzyme. The synthesized cDNA was then used for cRNA 140 synthesis andACCEPTED amplification
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