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

Jennifer Dahan (1, 2) , Florence Levillayer (1, 2) , Tian Xia (2) , Yann Nouët (1) , Catherine Werts (3) , Martine Fanton d'Andon (3) , Minou Adib-Conquy (4) , Anne-Marie Cassard-Doulcier (5) , Varun Khanna (6) , Ju Chen (7) , Thierry Tordjmann (8) , Marie-Annick Buendia (1) , Grégory Jouvion (9) , Yu Wei (1, 2)

1 Oncogenèse et Virologie Moléculaire
2 PVHB - Pathogenèse des Virus de l'Hépatite B
3 BGPB - Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall
4 Cytokines et Inflammation
5 Cytokines, chimiokines et immunopathologie
6 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
7 MED - UC San Diego - Department of Medicine [Univ California San Diego]
8 Signalisation calcique et interactions cellulaires dans le foie
9 Histopathologie humaine et Modèles animaux

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.

Mots clés: FHL2; TGF-β1; fibrosis; transcription regulation

Domaines: Biochimie, Biologie Moléculaire

Jennifer Dahan, Florence Levillayer, Tian Xia, Yann Nouët, Catherine Werts, et al.. LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression. Molecular and Cellular Biology, 2017, 37 (10), pp.e00636-16. ⟨10.1128/MCB.00636-16⟩. ⟨pasteur-02572332⟩