From Differential DNA Methylation in COPD to Mitochondria: Regulation of AHRR Expression Affects Airway Epithelial Response to Cigarette Smoke.

Chen, Q; Nwozor, KO; van den Berge, M; Slebos, D-J; Faiz, A; Jonker, MR; Boezen, HM; Heijink, IH; de Vries, M

From Differential DNA Methylation in COPD to Mitochondria: Regulation of AHRR Expression Affects Airway Epithelial Response to Cigarette Smoke.

Chen, Q Nwozor, KO van den Berge, M Slebos, D-J Faiz, A

Jonker, MR Boezen, HM Heijink, IH de Vries, M

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Publisher:: MDPI
Publication Type:: Journal Article
Citation:: Cells, 2022, 11, (21), pp. 3423
Issue Date:: 2022-10-29

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Field	Value	Language
dc.contributor.author	Chen, Q
dc.contributor.author	Nwozor, KO
dc.contributor.author	van den Berge, M
dc.contributor.author	Slebos, D-J
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Jonker, MR
dc.contributor.author	Boezen, HM
dc.contributor.author	Heijink, IH
dc.contributor.author	de Vries, M
dc.date.accessioned	2023-02-03T00:24:53Z
dc.date.available	2022-10-27
dc.date.available	2023-02-03T00:24:53Z
dc.date.issued	2022-10-29
dc.identifier.citation	Cells, 2022, 11, (21), pp. 3423
dc.identifier.issn	2073-4409
dc.identifier.issn	2073-4409
dc.identifier.uri	http://hdl.handle.net/10453/165871
dc.description.abstract	Cigarette smoking causes hypomethylation of the gene Aryl Hydrocarbon Receptor Repressor (AHRR), which regulates detoxification and oxidative stress-responses. We investigated whether AHRR DNA methylation is related to chronic obstructive pulmonary disease (COPD) and studied its function in airway epithelial cells (AECs). The association with COPD was assessed in blood from never and current smokers with/without COPD, and in AECs from ex-smoking non-COPD controls and GOLD stage II-IV COPD patients cultured with/without cigarette smoke extract (CSE). The effect of CRISPR/Cas9-induced AHRR knockout on proliferation, CSE-induced mitochondrial membrane potential and apoptosis/necrosis in human bronchial epithelial 16HBE cells was studied. In blood, DNA methylation of AHRR at cg05575921 and cg21161138 was lower in smoking COPD subjects than smoking controls. In vitro, AHRR DNA methylation at these CpG-sites was lower in COPD-derived than control-derived AECs only upon CSE exposure. Upon AHRR knockout, we found a lower proliferation rate at baseline, stronger CSE-induced decrease in mitochondrial membrane potential, and higher CSE-induced late apoptosis/necroptosis. Together, our results show lower DNA methylation of AHRR upon smoking in COPD patients compared to non-COPD controls. Our data suggest that higher airway epithelial AHRR expression may lead to impaired cigarette smoke-induced mitochondrial dysfunction and apoptosis/necroptosis, potentially promoting unprogrammed/immunogenic cell death.
dc.format	Electronic
dc.language	eng
dc.publisher	MDPI
dc.relation.ispartof	Cells
dc.relation.isbasedon	10.3390/cells11213423
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Humans
dc.subject.mesh	Basic Helix-Loop-Helix Transcription Factors
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Mitochondria
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Receptors, Aryl Hydrocarbon
dc.subject.mesh	Repressor Proteins
dc.subject.mesh	Tobacco
dc.subject.mesh	Mitochondria
dc.subject.mesh	Humans
dc.subject.mesh	Tobacco
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Receptors, Aryl Hydrocarbon
dc.subject.mesh	Repressor Proteins
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Basic Helix-Loop-Helix Transcription Factors
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	Humans
dc.subject.mesh	Basic Helix-Loop-Helix Transcription Factors
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	DNA Methylation
dc.subject.mesh	Mitochondria
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Receptors, Aryl Hydrocarbon
dc.subject.mesh	Repressor Proteins
dc.subject.mesh	Tobacco
dc.title	From Differential DNA Methylation in COPD to Mitochondria: Regulation of AHRR Expression Affects Airway Epithelial Response to Cigarette Smoke.
dc.type	Journal Article
utslib.citation.volume	11
utslib.location.activity	Switzerland
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
dc.date.updated	2023-02-03T00:24:47Z
pubs.issue	21
pubs.publication-status	Published online
pubs.volume	11
utslib.citation.issue	21

Abstract:

Cigarette smoking causes hypomethylation of the gene Aryl Hydrocarbon Receptor Repressor (AHRR), which regulates detoxification and oxidative stress-responses. We investigated whether AHRR DNA methylation is related to chronic obstructive pulmonary disease (COPD) and studied its function in airway epithelial cells (AECs). The association with COPD was assessed in blood from never and current smokers with/without COPD, and in AECs from ex-smoking non-COPD controls and GOLD stage II-IV COPD patients cultured with/without cigarette smoke extract (CSE). The effect of CRISPR/Cas9-induced AHRR knockout on proliferation, CSE-induced mitochondrial membrane potential and apoptosis/necrosis in human bronchial epithelial 16HBE cells was studied. In blood, DNA methylation of AHRR at cg05575921 and cg21161138 was lower in smoking COPD subjects than smoking controls. In vitro, AHRR DNA methylation at these CpG-sites was lower in COPD-derived than control-derived AECs only upon CSE exposure. Upon AHRR knockout, we found a lower proliferation rate at baseline, stronger CSE-induced decrease in mitochondrial membrane potential, and higher CSE-induced late apoptosis/necroptosis. Together, our results show lower DNA methylation of AHRR upon smoking in COPD patients compared to non-COPD controls. Our data suggest that higher airway epithelial AHRR expression may lead to impaired cigarette smoke-induced mitochondrial dysfunction and apoptosis/necroptosis, potentially promoting unprogrammed/immunogenic cell death.

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http://hdl.handle.net/10453/165871