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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

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 3

TGF-β and Wnt5A pathways are activated in CFIm25-knockdown fibroblasts.

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TGF-β and Wnt5A pathways are activated in CFIm25-knockdown fibroblasts.
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(A) The dPAS usage of CFIm25 targets involved in TGF-β (TGFBR1) and Wnt (WNT5A and FZD2) pathways was verified by qRT-PCR. n = 3 biological replicates. *P < 0.05 one sample t test versus 0. (B) RNA-Seq read density for a representative target (FZD2) is shown in control and CFIm25-knockdown CCD8-Lu cells. n = 3 biological replicates. P < 0.05, by 1-sample t test versus 0. Western blotting was performed to determine protein levels of (C) CFIm25 and TGF-βR1 and (D) Wnt5A and FZD2 in CFIm25-knockdown CCD8-Lu cells. (E) The dPAS usage of CFIm25 targets was determined using qRT-PCR in primary healthy (CCD8-Lu) or IPF fibroblasts (LL97A). n = 3 biological replicates. *P < 0.05, by 1-sample t test versus 0. (F and G) Western blotting was performed to determine protein levels of CFIm25, TGF-βR1, Wnt5A, and FZD2 in primary healthy (CCD8-Lu) and IPF fibroblasts (LL97A) (F) and IPF lungs with different levels of CFIm25 (G).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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