Cigarette smoking-associated isoform switching and 3' UTR lengthening via alternative polyadenylation

Zhonghui Xu; John Platig; Sool Lee; Adel Boueiz; Rob Chase; Dhawal Jain; Andrew Gregory; Rahul Suryadevara; Seth Berman; Russell Bowler; Craig P Hersh; Alain Laederach; Peter J Castaldi; COPDGene Investigators

doi:10.1016/j.ygeno.2021.11.004

Cigarette smoking-associated isoform switching and 3' UTR lengthening via alternative polyadenylation

Genomics. 2021 Nov;113(6):4184-4195. doi: 10.1016/j.ygeno.2021.11.004. Epub 2021 Nov 8.

Authors

Affiliations

¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
³ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Pulmonary Drug Discovery Laboratory, Bayer US LLC. Pharmaceuticals, Research & Development, Boston, MA, USA.
⁵ Northeastern University, Boston, MA, USA.
⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Northeastern University, Boston, MA, USA.
⁷ Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA.
⁸ Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: peter.castaldi@channing.harvard.edu.

Abstract

Cigarette smoking induces a profound transcriptomic and systemic inflammatory response. Previous studies have focused on gene level differential expression of smoking, but the genome-wide effects of smoking on alternative isoform regulation have not yet been described. We conducted RNA sequencing in whole-blood samples of 454 current and 767 former smokers in the COPDGene Study, and we analyzed the effects of smoking on differential usage of isoforms and exons. At 10% FDR, we detected 3167 differentially expressed genes, 945 differentially used isoforms and 160 differentially used exons. Isoform switch analysis revealed widespread 3' UTR lengthening associated with cigarette smoking. The lengthening of these 3' UTRs was consistent with alternative usage of distal polyadenylation sites, and these extended 3' UTR regions were significantly enriched with functional sequence elements including microRNA and RNA-protein binding sites. These findings warrant further studies on alternative polyadenylation events as potential biomarkers and novel therapeutic targets for smoking-related diseases.

Keywords: Alternative polyadenylation; Smoking; Transcriptomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

MeSH terms

3' Untranslated Regions
Cigarette Smoking* / adverse effects
Cigarette Smoking* / genetics
Polyadenylation*
Protein Isoforms / genetics
Smoking / adverse effects
Smoking / genetics

Substances

3' Untranslated Regions
Protein Isoforms

Abstract

Publication types

MeSH terms

Substances

Grants and funding