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

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
• transcription regulation
• fibrosis

We dedicate this paper to Minou Adib-Conquy.

We dedicate this paper to Minou Adib-Conquy.

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00636-16.

ACKNOWLEDGMENTS

We thank Sophie Lotersztajn and Fatima Teixeira-Clerc for insightful discussions. We are grateful to Jean-Marc Panaud for technical help.

This work was funded in part by the French Ligue contre le Cancer, Comité de Paris, the Fondation ARC pour la Recherche sur le Cancer (ARC), and the Institut National du Cancer (INCA). J.D. was supported by the French Ministère de l'Enseignement Supérieur et de la Recherche, Y.N. was supported by the Cancéropôle Ile-de-France, and T.X. was supported by Total Foundation.