BET proteins are associated with the induction of small airway fibrosis in COPD

Autor: Karosham D. Reddy, Sandra Rutting, Corry-Anke Brandsma, Dikaia Xenaki, Jack Bozier, Brian G. Oliver, Yik Lung Chan, Hui Chen, Razia Zakarya, Ian M. Adcock, Roy R Woldhuis, David Van Ly
Přispěvatelé: Groningen Research Institute for Asthma and COPD (GRIAC)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Pulmonary and Respiratory Medicine
respiratory muscles
Respiratory System
Myocytes
Smooth Muscle
TRANSFER-COEFFICIENT KCO
DISEASE
Epigenesis
Genetic
COPD ÀÜ mechanisms
Histone H4
Histones
Transforming Growth Factor beta1
03 medical and health sciences
Histone H3
Pulmonary Disease
Chronic Obstructive
0302 clinical medicine
DIFFUSING-CAPACITY
Medicine
Humans
Epigenetics
BRONCHODILATOR RESPONSE
Promoter Regions
Genetic
CARBON-MONOXIDE
Cells
Cultured
030304 developmental biology
0303 health sciences
lung physiology
biology
exercise
business.industry
1103 Clinical Sciences
Histone acetyltransferase
respiratory system
musculoskeletal system
REFERENCE VALUES
Cell biology
Extracellular Matrix
respiratory tract diseases
COPD pathology
Histone
030228 respiratory system
Acetylation
biology.protein
Histone deacetylase
business
Chromatin immunoprecipitation
MAXIMAL INSPIRATORY PRESSURE
Zdroj: Thorax, 76(7), 647-655. BMJ PUBLISHING GROUP
ISSN: 0040-6376
Popis: RationaleIn 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.ObjectivesDetermine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).MethodsPrimary 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 resultsCOPD 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.ConclusionsBET 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.
Databáze: OpenAIRE
Externí odkaz: