Dahan Jennifer, Levillayer Florence, Xia Tian, Nouët Yann, Werts Catherine, Fanton d'Andon Martine, Adib-Conquy Minou, Cassard-Doulcier Anne-Marie, Khanna Varun, Chen Ju, Tordjmann Thierry, Buendia Marie-Annick, Jouvion Grégory, Wei Yu
Unité d'Oncogenèse et Virologie Moléculaire, Institut Pasteur, Paris, France.
Laboratoire de Pathogenèse des Virus de l'Hépatite B, Institut Pasteur, Paris, France.
Mol Cell Biol. 2017 May 2;37(10). doi: 10.1128/MCB.00636-16. Print 2017 May 15.
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 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 mice. We tested the impact of Fhl2 loss on hepatic fibrogenesis that involves TGF-β1 activation. 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.
转化生长因子β1（TGF-β1）是许多生物学过程中的主要细胞因子，包括组织稳态、上皮-间质转化和伤口修复。在此，我们报道四半LIM结构域蛋白2（FHL2）是TGF-β1表达的关键调节因子。FHL2缺乏DNA结合结构域，是一种转录辅因子，根据细胞和启动子背景发挥共激活因子或共抑制因子的作用。我们检测到FHL2与TGF-β1启动子的关联，在报告基因分析中，该启动子在[具体细胞类型]细胞中的活性高于野生型（WT）细胞。FHL2的过表达消除了TGF-β1启动子的激活，而TGF-β1基因转录的上调与FHL2在启动子上的占有率降低相关。此外，FHL2的缺失促进了RNA聚合酶II在TGF-β1启动子上的募集，这表明FHL2可能参与了TGF-β1基因转录调控中的染色质重塑。在[具体小鼠品系]小鼠的肝脏中证实了TGF-β1 mRNA和细胞因子表达的增强。我们测试了Fhl2缺失对涉及TGF-β1激活的肝纤维化的影响。[具体小鼠品系]小鼠比其WT同窝小鼠发生更严重的纤维化。这些结果证明了FHL2对TGF-β1表达的抑制作用，并有助于理解TGF-β介导的纤维化反应。
