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Original research
BET proteins are associated with the induction of small airway fibrosis in COPD
  1. Razia Zakarya1,2,
  2. Yik L Chan2,
  3. Sandra Rutting3,
  4. Karosham Reddy1,2,
  5. Jack Bozier1,2,
  6. Roy R Woldhuis1,2,4,
  7. Dikaia Xenaki1,
  8. David Van Ly5,
  9. Hui Chen2,
  10. Corry-Anke Brandsma4,
  11. Ian M Adcock6,
  12. Brian G Oliver1,2
  1. 1 Respiratory Cell and Molecular Biology, Woolcock Institute of Medical Research, Glebe, New South Wales, Australia
  2. 2 School of Life Sciences, University of Technology Sydney, Ultimo, New South Wales, Australia
  3. 3 Airway Physiology and Imaging Group, Woolcock Institute of Medical Research, Glebe, New South Wales, Australia
  4. 4 Pathology and Medical Biology, University Medical Centre Groningen, Groningen, Groningen, The Netherlands
  5. 5 Genome Integrity Unit, Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales, Australia
  6. 6 Airways Disease, Respiratory Cell & Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
  1. Correspondence to Dr Razia Zakarya, Respiratory Cell and Molecular Biology, Woolcock Institute of Medical Research, Glebe, NSW 2037, Australia; Razia.Zakarya{at}sydney.edu.au

Abstract

Rationale In COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed.

Objectives Determine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).

Methods Primary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed.

Measurements and main results COPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC.

Conclusions BET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.

  • COPD ÀÜ mechanisms
  • COPD pathology

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • Contributors RZ, SR, KR, YLC, JB, RRW and DX performed experiments. RZ analysed data, prepared figures and drafted manuscript. RZ, BGO and IA interpreted results of experiments. DVL, C-AB, IA and BGO edited and revised manuscript. RZ, SR, KR, YLC, JB, RRW, DVL, HC, C-AB, IA and BGO approved final version of manuscript. RZ, C-AB, IA and BGO conceived and designed research.

  • Funding This work was supported by the National Health and Medical Research Council, Australia (Grant ID: 1104704).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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