Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation

Tingting Weng, Jingjing Huang, Eric J. Wagner, Junsuk Ko, Minghua Wu, Nancy E. Wareing, Yu Xiang, Ning Yuan Chen, Ping Ji, Jose G. Molina, Kelly A. Volcik, Leng Han, Maureen D. Mayes, Michael R. Blackburn, Shervin Assassi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
JournalThe Journal of experimental medicine
Volume217
Issue number2
DOIs
StatePublished - Feb 3 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation'. Together they form a unique fingerprint.

Cite this