Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation
Abstract
Systemic sclerosis (SSc; scleroderma) is a multisystem fibrotic disease. The mammalian cleavage factor I 25-kD subunit (CFIm25; encoded by NUDT21) is a key regulator of alternative polyadenylation, and its depletion causes predominantly 3′UTR shortening through loss of stimulation of distal polyadenylation sites. A shortened 3′UTR will often lack microRNA target sites, resulting in increased mRNA translation due to evasion of microRNA-mediated repression. Herein, we report that CFlm25 is downregulated in SSc skin, primary dermal fibroblasts, and two murine models of dermal fibrosis. Knockdown of CFIm25 in normal skin fibroblasts is sufficient to promote the 3′UTR shortening of key TGFβ-regulated fibrotic genes and enhance their protein expression. Moreover, several of these fibrotic transcripts show 3′UTR shortening in SSc skin. Finally, mice with CFIm25 deletion in fibroblasts show exaggerated skin fibrosis upon bleomycin treatment, and CFIm25 restoration attenuates bleomycin-induced skin fibrosis. Overall, our data link this novel RNA-processing mechanism to dermal fibrosis and SSc pathogenesis.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 22, 2019
- Source ID
- 10.1084/jem.20181384
Entities
People
- Eric J. Wagner
- Jingjing Huang
- Jose G. Molina
- Junsuk Ko
- Kelly A. Volcik
- Leng Han
- Maureen D Mayes
- Michael R. Blackburn
- Minghua Wu
- Nancy E. Wareing
- Ning-yuan Chen
- Ping Ji
- Shervin Assassi
- Tingting Weng
- Yu Xiang
Organizations
- Cancer Prevention and Research Institute of Texas
- Nanjing Medical University
- National Institutes of Health
- United States Department of Defense
- University of Texas Health Science Center at Houston
- University of Texas Medical Branch