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.
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
Usage data is cumulative from February 2019 through October 2019.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.