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ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis.

Ilaria Laudadio1, Alex Bastianelli1, Valerio Fulci1

  • 1Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy.

International Journal of Molecular Sciences
|September 23, 2022
PubMed
Summary

ZNF281, a key regulator, drives intestinal fibrosis by promoting fibroblast activation and differentiation in inflammatory bowel disease. This study reveals its crucial role in extracellular matrix remodeling and gut fibrosis progression.

Keywords:
Crohn’s diseaseZNF281fibroblastsintestinal fibrosis

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Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Fibrosis Research

Background:

  • Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases characterized by intestinal fibrosis.
  • The molecular mechanisms underlying intestinal fibrosis, particularly in CD, remain unclear.
  • ZNF281, a known EMT-inducing transcription factor, is implicated in stemness and cancer, suggesting a potential role in fibrosis.

Purpose of the Study:

  • To investigate the role of ZNF281 in intestinal fibrogenesis in vivo and in vitro.
  • To elucidate the molecular mechanisms by which ZNF281 contributes to gut fibrosis.

Main Methods:

  • In vivo study: Chronic colitis induced in C57BL/6J mice using dextran sulfate sodium (DSS).
  • In vitro study: Human colon fibroblast cell line (CCD-18Co) activated by TGFβ1; ZNF281 knockdown via siRNA.
  • RNA-sequencing performed to identify genes regulated by TGFβ1 via ZNF281 in activated fibroblasts.

Main Results:

  • ZNF281 expression was significantly increased in fibrotic murine colon and TGFβ1-activated human colon fibroblasts.
  • Abrogation of ZNF281 in activated fibroblasts altered gene expression in pathways related to fibroblast activation and myofibroblast differentiation.
  • ZNF281 was shown to transcriptionally control extracellular matrix (ECM) composition, remodeling, and cell contraction.

Conclusions:

  • ZNF281 is a critical regulator of colon fibroblast activation and myofibroblast differentiation in response to fibrotic stimuli.
  • ZNF281 plays a significant role in the onset and progression of gut fibrosis.
  • This study highlights a novel function of ZNF281 in the pathogenesis of intestinal fibrosis.