title: Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (PVT1) as a novel regulator of the asthmatic phenotype in human airway smooth muscle.
abstract: BACKGROUND
  The mechanism underlying nonsevere and severe asthma remains unclear, although it is commonly associated with increased airway smooth muscle (ASM) mass. Long noncoding RNAs (lncRNAs) are known to be important in regulating healthy primary airway smooth muscle cells (ASMCs), whereas changed expression has been observed in CD8 T cells from patients with severe asthma.
  
  
  METHODS
  Primary ASMCs were isolated from healthy subjects (n = 9) and patients classified as having nonsevere (n = 9) or severe (n = 9) asthma. ASMCs were exposed to dexamethasone and FCS. mRNA and lncRNA expression was measured by using a microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine relevant biological pathways. Finally, the lncRNA plasmacytoma variant translocation 1 (PVT1) was inhibited by transfection of primary ASMCs with small interfering RNAs, and the effect on ASMC phenotype was examined.
  
  
  RESULTS
  The mRNA expression profile was significantly different between patient groups after exposure to dexamethasone and FCS, and these were associated with biological pathways that might be relevant to the pathogenesis of asthma, including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in lncRNA expression, yet the expression of only one lncRNA (PVT1) is decreased in patients with corticosteroid-sensitive nonsevere asthma and increased in patients with corticosteroid-insensitive severe asthma. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASMCs from patients with severe asthma.
  
  
  CONCLUSIONS
  lncRNAs are associated with the aberrant phenotype observed in ASMCs from asthmatic patients. Targeting PVT1 might be effective in reducing airway remodeling in asthmatic patients.
authors.affiliation: Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Austin
authors.affiliation: Respiratory Research Group, University Hospital of South Manchester, University of Manchester, Manchester, United Kingdom.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tsitsiou
authors.affiliation: Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Boardman
authors.affiliation: Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Jones
authors.affiliation: Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom; Respiratory Research Group, University Hospital of South Manchester, University of Manchester, Manchester, United Kingdom; Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lindsay
authors.affiliation: Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
authors.affiliation: Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Institute of Child Health, London, United Kingdom. Electronic address: mark.perry@ucl.ac.uk.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Perry
mesh_terms: D000328:Adult; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C489427:MYC protein, human; C521123:PVT1 long-non-coding RNA, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: Asthma; IL-6; PVT1; airway smooth muscle; long noncoding RNA; proliferation; transcriptome