ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis
| Autor: | Ilaria Laudadio, Alex Bastianelli, Valerio Fulci, Claudia Carissimi, Eleonora Colantoni, Francesca Palone, Roberta Vitali, Elisa Lorefice, Salvatore Cucchiara, Anna Negroni, Laura Stronati |
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| Rok vydání: | 2022 |
| Předmět: |
Colon
Organic Chemistry Dextran Sulfate General Medicine Fibroblasts Colitis Fibrosis Catalysis Computer Science Applications Inorganic Chemistry Mice Inbred C57BL Repressor Proteins Mice Zinc Crohn Disease Transforming Growth Factor beta Animals Humans intestinal fibrosis Crohn’s disease fibroblasts ZNF281 Physical and Theoretical Chemistry RNA Small Interfering Molecular Biology Spectroscopy Transcription Factors |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 18; Pages: 10261 |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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