title: 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 inFhl2-/-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 ofFhl2-/-mice. We tested thein vivoimpact 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.
authors.affiliation: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France.|Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dahan
authors.affiliation: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France.|Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Levillayer
authors.affiliation: Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Nouët
authors.affiliation: Unité de Biologie et Génétique de la Paroi Bactérienne, Institut Pasteur, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Werts
authors.affiliation: Unité de Biologie et Génétique de la Paroi Bactérienne, Institut Pasteur, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Fanton d'Andon
authors.affiliation: Unité de Recherche Cytokines et Inflammation, Institut Pasteur, Paris, France.
authors.forename: Minou
authors.initials: M
authors.lastname: Adib-Conquy
authors.affiliation: INSERM U996 Inflammation, Université Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cassard-Doulcier
authors.affiliation: Hub Bioinformatique et Biostatistique-C3BI, USR 3756 IP CNRS, Institut Pasteur, Paris, France.
authors.forename: Varun
authors.initials: V
authors.lastname: Khanna
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: INSERM U757, Université Paris-Sud, Université Paris-Saclay, Orsay, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Tordjmann
authors.affiliation: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France.
authors.forename: Marie-Annick
authors.initials: MA
authors.lastname: Buendia
authors.affiliation: Unité d'Histopathologie Humaine et Modèles Animaux, Institut Pasteur, Paris, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Jouvion
authors.affiliation: Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France yu.wei@pasteur.fr.|Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D060850:LIM-Homeodomain Proteins / Q000502:physiology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1
keywords: FHL2; TGF-β1; fibrosis; transcription regulation