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Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation
Tingting Weng, … , Eric J. Wagner, Michael R. Blackburn
Tingting Weng, … , Eric J. Wagner, Michael R. Blackburn
Published February 28, 2019
Citation Information: J Clin Invest. 2019;129(5):1984-1999. https://doi.org/10.1172/JCI122106.
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Research Article Pulmonology Article has an altmetric score of 3

Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation

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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.

Authors

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 Han, Wei Li, Shervin Assassi, Harry Karmouty-Quintana, Eric J. Wagner, Michael R. Blackburn

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Figure 8

Col1a1-CreER-CFIm25fl/fl mice have more severe pulmonary fibrosis upon o.p.a. bleomycin injection.

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Col1a1-CreER-CFIm25fl/fl mice have more severe pulmonary fibrosis upon ...
(A) Diagram shows the mouse treatment timeline. Four- to six-week-old Col1a1-CreER-CFIm25fl/fl mice and age- and sex-matched littermate controls were administrated 75 mg/kg tamoxifen (i.p.) daily for 5 days to induce Cre activation. After 1 week, mice were injected with PBS or bleomycin through o.p.a. instillation. Lungs were collected for analysis 21 days after the first bleomycin injection. (B) Western blot shows CFIm25, COL1, FN, TGF-βR1, Wnt5A, and FZD2 expression in the lungs of control and Col1a1-CreER-CFIm25fl/+ mice. qRT-PCR (C) and a Sircol assay (D) were carried out to analyze the levels of pulmonary fibrosis. (E) Tissue damping, tissue elastase, resistance, compliance, inspiratory capacity, and Newtonian resistance were analyzed using the flexiVent system. (F) Masson’s trichrome and α-SMA staining indicated collagen deposition and myofibroblast differentiation. Scale bars: 200 μm. (G) Blinded Ashcroft assays were performed to quantify the pulmonary fibrosis observed on Masson’s trichrome–stained slides. *P < 0.05, by unpaired t test with equal variance. n > 4 biological replicates.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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