LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression

Mol Cell Biol. 2017 May 2;37(10):e00636-16. doi: 10.1128/MCB.00636-16. Print 2017 May 15.

Abstract

Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-β1 promoter, which showed higher activity in Fhl2-/- cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-β1 promoter, whereas the upregulation of TGF-β1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-β1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-β1 gene transcription. Enhanced expression of TGF-β1 mRNA and cytokine was evidenced in the livers of Fhl2-/- mice. We tested the in vivo impact of Fhl2 loss on hepatic fibrogenesis that involves TGF-β1 activation. Fhl2-/- mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-β1 expression and contribute to the understanding of the TGF-β-mediated fibrogenic response.

Keywords: FHL2; TGF-β1; fibrosis; transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Expression Regulation*
  • LIM-Homeodomain Proteins / physiology*
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Proteins / physiology*
  • Promoter Regions, Genetic*
  • Transcription Factors / physiology*
  • Transcriptional Activation
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Fhl2 protein, mouse
  • LIM-Homeodomain Proteins
  • Muscle Proteins
  • Transcription Factors
  • Transforming Growth Factor beta1