Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation

Tingting Weng, Junsuk Ko, Chioniso P. Masamha, Zheng Xia, Yu Xiang, Ning yuan Chen, Jose G. Molina, Scott Collum, Tinne C. Mertens, Fayong Luo, Kemly Philip, Jonathan Davies, Jingjing Huang, Cory Wilson, Rajarajan A. Thandavarayan, Brian A. Bruckner, Soma S.K. Jyothula, Kelly A. Volcik, Lei Li, Leng HanWei Li, Shervin Assassi, Harry Karmouty-Quintana, Eric Wagner, Michael R. Blackburn

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a poor prognosis and few treatment options. Pathological remodeling of the extracellular matrix (ECM) is a key factor that drives the disease pathogenesis, although the underlying mechanisms remain unknown. Alternative polyadenylation (APA) has recently been shown to play a major role in cellular responses to stress by driving the expression of fibrotic factors through the alteration of miRNA sensitivity, but a connection to IPF has not been established. Here, we demonstrated that CFIm25, a global regulator of APA, was downregulated in the lungs of patients with IPF and mice with pulmonary fibrosis, with its expression selectively reduced in α–smooth muscle actin–positive (α-SMA–positive) fibroblasts. Following CFIm25 knockdown in healthy human lung fibroblasts, we identified 808 genes with shortened 3′-UTRs, including those involved in the TGF-β signaling pathway, the Wnt signaling pathway, and cancer pathways. The expression of key profibrotic factors was suppressed by CFIm25 overexpression in IPF fibroblasts. Finally, we demonstrated that deletion of CFIm25 in fibroblasts or myofibroblast precursors using either the Col1a1 or the Foxd1 promoter enhanced pulmonary fibrosis after bleomycin exposure. Collectively, our results identified CFIm25 downregulation as an important mechanism for elevating profibrotic gene expression in pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)1984-1999
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number5
DOIs
StatePublished - May 1 2019

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Idiopathic Pulmonary Fibrosis
Polyadenylation
Pulmonary Fibrosis
Fibroblasts
Down-Regulation
Lung
Wnt Signaling Pathway
Myofibroblasts
Bleomycin
3' Untranslated Regions
MicroRNAs
Extracellular Matrix
Smooth Muscle
Gene Expression
Genes
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Weng, T., Ko, J., Masamha, C. P., Xia, Z., Xiang, Y., Chen, N. Y., ... Blackburn, M. R. (2019). Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation. Journal of Clinical Investigation, 129(5), 1984-1999. https://doi.org/10.1172/JCI122106

Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation. / Weng, Tingting; Ko, Junsuk; Masamha, Chioniso P.; Xia, Zheng; Xiang, Yu; Chen, Ning yuan; Molina, Jose G.; Collum, Scott; Mertens, Tinne C.; Luo, Fayong; Philip, Kemly; Davies, Jonathan; Huang, Jingjing; Wilson, Cory; Thandavarayan, Rajarajan A.; Bruckner, Brian A.; Jyothula, Soma S.K.; Volcik, Kelly A.; Li, Lei; Han, Leng; Li, Wei; Assassi, Shervin; Karmouty-Quintana, Harry; Wagner, Eric; Blackburn, Michael R.

In: Journal of Clinical Investigation, Vol. 129, No. 5, 01.05.2019, p. 1984-1999.

Research output: Contribution to journalArticle

Weng, T, Ko, J, Masamha, CP, Xia, Z, Xiang, Y, Chen, NY, Molina, JG, Collum, S, Mertens, TC, Luo, F, Philip, K, Davies, J, Huang, J, Wilson, C, Thandavarayan, RA, Bruckner, BA, Jyothula, SSK, Volcik, KA, Li, L, Han, L, Li, W, Assassi, S, Karmouty-Quintana, H, Wagner, E & Blackburn, MR 2019, 'Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation', Journal of Clinical Investigation, vol. 129, no. 5, pp. 1984-1999. https://doi.org/10.1172/JCI122106
Weng, Tingting ; Ko, Junsuk ; Masamha, Chioniso P. ; Xia, Zheng ; Xiang, Yu ; Chen, Ning yuan ; Molina, Jose G. ; Collum, Scott ; Mertens, Tinne C. ; Luo, Fayong ; Philip, Kemly ; Davies, Jonathan ; Huang, Jingjing ; Wilson, Cory ; Thandavarayan, Rajarajan A. ; Bruckner, Brian A. ; Jyothula, Soma S.K. ; Volcik, Kelly A. ; Li, Lei ; Han, Leng ; Li, Wei ; Assassi, Shervin ; Karmouty-Quintana, Harry ; Wagner, Eric ; Blackburn, Michael R. / Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 5. pp. 1984-1999.
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AU - Ko, Junsuk

AU - Masamha, Chioniso P.

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AU - Xiang, Yu

AU - Chen, Ning yuan

AU - Molina, Jose G.

AU - Collum, Scott

AU - Mertens, Tinne C.

AU - Luo, Fayong

AU - Philip, Kemly

AU - Davies, Jonathan

AU - Huang, Jingjing

AU - Wilson, Cory

AU - Thandavarayan, Rajarajan A.

AU - Bruckner, Brian A.

AU - Jyothula, Soma S.K.

AU - Volcik, Kelly A.

AU - Li, Lei

AU - Han, Leng

AU - Li, Wei

AU - Assassi, Shervin

AU - Karmouty-Quintana, Harry

AU - Wagner, Eric

AU - Blackburn, Michael R.

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