Epigenetic Modulation of Small Airway Fibrosis in Chronic Obstructive Pulmonary Disease

Zakarya, Razia

Epigenetic Modulation of Small Airway Fibrosis in Chronic Obstructive Pulmonary Disease

Zakarya, Razia

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Publication Type:: Thesis
Issue Date:: 2019

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Field	Value	Language
dc.contributor.author	Zakarya, Razia
dc.date.accessioned	2020-05-04T00:58:51Z
dc.date.available	2020-05-04T00:58:51Z
dc.date.issued	2019
dc.identifier.uri	http://hdl.handle.net/10453/140434
dc.description	University of Technology Sydney. Faculty of Science.	en_AU
dc.description.abstract	Chronic Obstructive Pulmonary Disease is commonly associated with cigarette smoke exposure in developed nations. However, research demonstrating that a minority proportion of smokers develop COPD alongside findings that show a stronger correlation between lung function and familial relation than smoke exposure demonstrates that the link between cigarette smoking and airway obstruction is not linear. Previous work from our lab has shown that airway mesenchymal cells of COPD patients produced more extracellular matrix (ECM), thereby contributing to small airway fibrosis. We hypothesise that the mechanisms underpinning increased ECM production in COPD was epigenetic. Using primary human airway smooth muscle cells, we carried out a microarray gene analysis to determine which ECM genes were aberrantly upregulated in COPD. We determined that transforming growth factor β1 (TGF-β1) stimulation lead to significantly higher induction of COL15A1 and TNC in COPD in vitro. Further, we carried out IHC analysis to show that collagen 15α1 and tenascin-C were deposed in the airway smooth muscle (ASM) layer in small airways of COPD patients. Upon quantifying amount of ECM protein deposed within the ASM layer, we determined that collagen 15α1 deposition was significantly higher in COPD airways; demonstrating that the ECM protein was aberrantly expressed in vivo. Investigating epigenetic modulations directed us towards studying specific acetyl-lysine histone modifications at the target gene promoter regions. We, for the first time, demonstrated that increased ECM expression in COPD is modulated by histone H4 acetylation induced upon stimulation with TGF-β1. Further, we found that the epigenetic reader, Brd4, plays a role in propagating the epigenetic mark to sustain prolonged COL15A1 and TNC expression.	en_AU
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/140434/2/02whole.pdf
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	au.edu.uts.lib/ppc
dc.rights	info:eu-repo/semantics/openAccess
dc.title	Epigenetic Modulation of Small Airway Fibrosis in Chronic Obstructive Pulmonary Disease	en_AU
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Chronic Obstructive Pulmonary Disease is commonly associated with cigarette smoke exposure in developed nations. However, research demonstrating that a minority proportion of smokers develop COPD alongside findings that show a stronger correlation between lung function and familial relation than smoke exposure demonstrates that the link between cigarette smoking and airway obstruction is not linear. Previous work from our lab has shown that airway mesenchymal cells of COPD patients produced more extracellular matrix (ECM), thereby contributing to small airway fibrosis. We hypothesise that the mechanisms underpinning increased ECM production in COPD was epigenetic. Using primary human airway smooth muscle cells, we carried out a microarray gene analysis to determine which ECM genes were aberrantly upregulated in COPD. We determined that transforming growth factor β1 (TGF-β1) stimulation lead to significantly higher induction of COL15A1 and TNC in COPD in vitro. Further, we carried out IHC analysis to show that collagen 15α1 and tenascin-C were deposed in the airway smooth muscle (ASM) layer in small airways of COPD patients. Upon quantifying amount of ECM protein deposed within the ASM layer, we determined that collagen 15α1 deposition was significantly higher in COPD airways; demonstrating that the ECM protein was aberrantly expressed in vivo. Investigating epigenetic modulations directed us towards studying specific acetyl-lysine histone modifications at the target gene promoter regions. We, for the first time, demonstrated that increased ECM expression in COPD is modulated by histone H4 acetylation induced upon stimulation with TGF-β1. Further, we found that the epigenetic reader, Brd4, plays a role in propagating the epigenetic mark to sustain prolonged COL15A1 and TNC expression.

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http://hdl.handle.net/10453/140434