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ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis

TitleZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2022
AuthorsLaudadio, I., Bastianelli A., Fulci V., Carissimi C., Colantoni Eleonora, Palone Francesca, Vitali Roberta, Lorefice E., Cucchiara S., Negroni Anna, and Stronati L.
JournalInternational Journal of Molecular Sciences
Keywordsacta2 protein, adam19 protein, alpha smooth muscle actin, alpha tropomyosin, animal cell, animal experiment, animal model, article, beta3 integrin, CCD-18Co cell line, cell activation, cell differentiation, collagen type 3 alpha 1, collagen type 4 alpha 1 chain, collagen type I alpha 1 chain, colon tissue, connective tissue growth factor, contractile protein, controlled study, cytokine, Dextran Sulfate, dextran sulfate sodium-induced colitis, down regulation, extracellular matrix, fgf protein, fibroblast, fibrogenesis, fibronectin, gastrointestinal tract, gelatinase B, Gene expression, gene silencing, genetic regulation, genetic transfection, human, human cell, in vitro study, in vivo study, interleukin 6, intestinal fibrosis, itga1 protein, itga11 protein, itga9 protein, male, messenger RNA, mouse, myh11 protein, myofibroblast, myoz1 protein, nonhuman, protein expression, protein protein interaction, proteinase, RNA sequencing, scleroprotein, seprase, serpine1 protein, Small interfering RNA, thbs1 protein, tns1 protein, transcription factor, transcription factor Snail, transforming growth factor beta1, unclassified drug, uvomorulin, vimentin, zinc finger protein, ZNF281 protein

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis. © 2022 by the authors.


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Citation KeyLaudadio2022