Alternative Splicing Is a Major Factor Shaping Transcriptome Diversity in Mild and Severe Chronic Obstructive Pulmonary Disease.

Khalenkow, D; Brandsma, C-A; Timens, W; Choy, DF; Grimbaldeston, MA; Rosenberger, CM; Slebos, D-J; Kerstjens, HAM; Faiz, A; Koppelman, GH; Nawijn, MC; van den Berge, M; Guryev, V

Alternative Splicing Is a Major Factor Shaping Transcriptome Diversity in Mild and Severe Chronic Obstructive Pulmonary Disease.

Khalenkow, D Brandsma, C-A Timens, W Choy, DF Grimbaldeston, MA Rosenberger, CM Slebos, D-J Kerstjens, HAM Faiz, A

Koppelman, GH Nawijn, MC van den Berge, M Guryev, V

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Publisher:: AMER THORACIC SOC
Publication Type:: Journal Article
Citation:: Am J Respir Cell Mol Biol, 2024, 70, (5), pp. 414-423
Issue Date:: 2024-05

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Field	Value	Language
dc.contributor.author	Khalenkow, D
dc.contributor.author	Brandsma, C-A
dc.contributor.author	Timens, W
dc.contributor.author	Choy, DF
dc.contributor.author	Grimbaldeston, MA
dc.contributor.author	Rosenberger, CM
dc.contributor.author	Slebos, D-J
dc.contributor.author	Kerstjens, HAM
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Koppelman, GH
dc.contributor.author	Nawijn, MC
dc.contributor.author	van den Berge, M
dc.contributor.author	Guryev, V
dc.date.accessioned	2024-11-22T00:37:58Z
dc.date.available	2024-11-22T00:37:58Z
dc.date.issued	2024-05
dc.identifier.citation	Am J Respir Cell Mol Biol, 2024, 70, (5), pp. 414-423
dc.identifier.issn	1044-1549
dc.identifier.issn	1535-4989
dc.identifier.uri	http://hdl.handle.net/10453/182045
dc.description.abstract	The role of alternative splicing in chronic obstructive pulmonary disease (COPD) is still largely unknown. We aimed to investigate the differences in alternatively splicing events between patients with mild-to-moderate and severe COPD compared with non-COPD control subjects and to identify splicing factors associated with aberrant alternative splicing in COPD. For this purpose, we performed genome-wide RNA-sequencing analysis of bronchial brushings from 23 patients with mild-to-moderate COPD, 121 with severe COPD, and 23 non-COPD control subjects. We found a significant difference in the frequency of alternative splicing events in patients with mild-to-moderate and severe COPD compared with non-COPD control subjects. There were from two to eight times (depending on event type) more differential alternative splicing events in the severe than in the mild-to-moderate stage. The severe COPD samples showed less intron retention and more exon skipping. It is interesting that the transcript levels of the top 10 differentially expressed splicing factors were significantly correlated with the percentage of many alternatively spliced transcripts in severe COPD. The aberrant alternative splicing in severe COPD was predicted to increase the overall protein-coding capacity of gene products. In conclusion, we observed large and significant differences in alternative splicing between bronchial samples of patients with COPD and control subjects, with more events observed in severe than in mild-to-moderate COPD. The changes in the expression of several splicing factors correlated with prevalence of alternative splicing in severe COPD. Alternative splicing can indirectly impact gene expression by changing the relative abundance of protein-coding isoforms potentially influencing pathophysiological changes. The results provide a better understanding of COPD-related alternative splicing changes.
dc.format	Print
dc.language	eng
dc.publisher	AMER THORACIC SOC
dc.relation.ispartof	Am J Respir Cell Mol Biol
dc.relation.isbasedon	10.1165/rcmb.2023-0296OC
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1102 Cardiorespiratory Medicine and Haematology
dc.subject.classification	Respiratory System
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.mesh	Humans
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Alternative Splicing
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Transcriptome
dc.subject.mesh	Aged
dc.subject.mesh	Middle Aged
dc.subject.mesh	Severity of Illness Index
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Exons
dc.subject.mesh	Humans
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Severity of Illness Index
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Alternative Splicing
dc.subject.mesh	Exons
dc.subject.mesh	Aged
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Transcriptome
dc.subject.mesh	Humans
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Alternative Splicing
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Transcriptome
dc.subject.mesh	Aged
dc.subject.mesh	Middle Aged
dc.subject.mesh	Severity of Illness Index
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Exons
dc.title	Alternative Splicing Is a Major Factor Shaping Transcriptome Diversity in Mild and Severe Chronic Obstructive Pulmonary Disease.
dc.type	Journal Article
utslib.citation.volume	70
utslib.location.activity	United States
utslib.for	1102 Cardiorespiratory Medicine and Haematology
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/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)
utslib.copyright.status	closed_access	*
dc.date.updated	2024-11-22T00:37:56Z
pubs.issue	5
pubs.publication-status	Published
pubs.volume	70
utslib.citation.issue	5

Abstract:

The role of alternative splicing in chronic obstructive pulmonary disease (COPD) is still largely unknown. We aimed to investigate the differences in alternatively splicing events between patients with mild-to-moderate and severe COPD compared with non-COPD control subjects and to identify splicing factors associated with aberrant alternative splicing in COPD. For this purpose, we performed genome-wide RNA-sequencing analysis of bronchial brushings from 23 patients with mild-to-moderate COPD, 121 with severe COPD, and 23 non-COPD control subjects. We found a significant difference in the frequency of alternative splicing events in patients with mild-to-moderate and severe COPD compared with non-COPD control subjects. There were from two to eight times (depending on event type) more differential alternative splicing events in the severe than in the mild-to-moderate stage. The severe COPD samples showed less intron retention and more exon skipping. It is interesting that the transcript levels of the top 10 differentially expressed splicing factors were significantly correlated with the percentage of many alternatively spliced transcripts in severe COPD. The aberrant alternative splicing in severe COPD was predicted to increase the overall protein-coding capacity of gene products. In conclusion, we observed large and significant differences in alternative splicing between bronchial samples of patients with COPD and control subjects, with more events observed in severe than in mild-to-moderate COPD. The changes in the expression of several splicing factors correlated with prevalence of alternative splicing in severe COPD. Alternative splicing can indirectly impact gene expression by changing the relative abundance of protein-coding isoforms potentially influencing pathophysiological changes. The results provide a better understanding of COPD-related alternative splicing changes.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/182045