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

Transforming growth factor beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 promoter, which showed higher activity in Fhl2(-/-) cells than in wildtype (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-beta 1 promoter, whereas the upregulation of TGF-beta 1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-beta 1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-beta 1 gene transcription. Enhanced expression of TGF-beta 1 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-beta 1 activation. Fhl2(-/-) mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-beta 1 expression and contribute to the understanding of the TGF-beta-mediated fibrogenic response.