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 journalArticle

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

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Polyadenylation
Fibrosis
Down-Regulation
Skin
3' Untranslated Regions
Fibroblasts
Bleomycin
MicroRNAs
Systemic Scleroderma
Protein Biosynthesis
RNA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation. / Weng, Tingting; Huang, Jingjing; Wagner, Eric J.; Ko, Junsuk; Wu, Minghua; Wareing, Nancy E.; Xiang, Yu; Chen, Ning Yuan; Ji, Ping; Molina, Jose G.; Volcik, Kelly A.; Han, Leng; Mayes, Maureen D.; Blackburn, Michael R.; Assassi, Shervin.

In: The Journal of experimental medicine, Vol. 217, No. 2, 03.02.2020.

Research output: Contribution to journalArticle

Weng, T, Huang, J, Wagner, EJ, Ko, J, Wu, M, Wareing, NE, Xiang, Y, Chen, NY, Ji, P, Molina, JG, Volcik, KA, Han, L, Mayes, MD, Blackburn, MR & Assassi, S 2020, 'Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation', The Journal of experimental medicine, vol. 217, no. 2. https://doi.org/10.1084/jem.20181384
Weng, Tingting ; Huang, Jingjing ; Wagner, Eric J. ; Ko, Junsuk ; Wu, Minghua ; Wareing, Nancy E. ; Xiang, Yu ; Chen, Ning Yuan ; Ji, Ping ; Molina, Jose G. ; Volcik, Kelly A. ; Han, Leng ; Mayes, Maureen D. ; Blackburn, Michael R. ; Assassi, Shervin. / Downregulation of CFIm25 amplifies dermal fibrosis through alternative polyadenylation. In: The Journal of experimental medicine. 2020 ; Vol. 217, No. 2.
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