Alternative Splicing Is a Major Factor Shaping Transcriptome Diversity in Mild and Severe COPD

Dmitry Khalenkow, Corry-Anke Brandsma, Wim Timens, David F Choy, Michele A Grimbaldeston, Carrie M Rosenberger, Dirk-Jan Slebos, Huib A M Kerstjens, Alen Faiz, Gerard H Koppelman, Martijn C Nawijn, Maarten van den Berge, Victor Guryev

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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 to non-COPD controls and to identify splicing factors associated with aberrant alternative splicing in COPD. For this purpose, we performed genome-wide RNA-seq analysis of bronchial brushings from 23 mild-to-moderate, 121 severe COPD patients, and 23 non-COPD controls. We found a significant difference in the frequency of alternative splicing events in mild-to-moderate and severe COPD compared to non-COPD controls. There were from 2x to 8x (depending on event type) more differential alternative splicing events in the severe than in the mild-to-moderate stage. The samples from severe COPD patients showed less intron retention and more exon skipping. Interestingly, 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 COPD and control individuals, 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 presented results provide a better understanding of COPD-related alternative splicing changes.

Original languageEnglish
Number of pages48
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Publication statusE-pub ahead of print - 5-Feb-2024

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