Histone deacetylase 4 is required for TGFβ1-induced myofibroblastic differentiation
Histone deacetylase 4 is required for TGFβ1-induced myofibroblastic differentiation
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DOI：
10.1016/j.bbamcr.2007.05.016
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发表时间：
2007-10-01
影响因子：
5.1
通讯作者：
Waltregny, David
中科院分区：
文献类型：
--
作者：
Glenisson, Wendy;Castronovo, Vincent;Waltregny, David
转化生长因子β 1（TGF β 1）是触发肌纤维母细胞（MF）分化的关键细胞因子，这是一个参与组织愈合以及病理状况如纤维化和癌症的过程。与细胞形状改变一起，TGF β 1介导的成纤维细胞向肌成纤维细胞的分化特征性地与平滑肌α-肌动蛋白（α-SMA）的新表达相关，α-SMA是一种增强其收缩活性的细胞骨架蛋白。几种细胞分化程序已与基因表达的表观遗传调控相关，包括基因甲基化和历史乙酰化。在此，我们试图研究组蛋白去乙酰化酶（HDAC）在TGF β 1诱导的MY分化中的作用。我们发现TSA是I类和II类HDAC的全局抑制剂，可阻止培养的人皮肤成纤维细胞中TGF β 1介导的α-SMA转录物和蛋白质表达以及形态学变化。为了鉴定参与MF分化的HDAC，在暴露于TGF β 1的成纤维细胞中研究了使用RNA干扰的特异性HDAC沉默（HDAC 1至HDAC 8）的影响。在测试的八种HDAC中，HDAC 4、HDAC 6和HDAC 8表达的沉默损害了TGF β 1诱导的α-SMA表达。HDAC 4沉默最有效地消除了α-SMA表达，也防止了TGF β 1介导的形态学变化。HDAC 4的强制下调刺激了5 '-TG-3'-相互作用因子（TGIF）和TGIF 2同源异型蛋白（TGF β信号传导途径的两种已知内源性阻遏物）的表达，但不刺激抑制性Smad 7的表达。总的来说，这些数据表明HDAC 4是MF分化的重要表观遗传调节因子，并揭示HDAC 4作为治疗MF相关疾病的潜在靶标。(C)2007年由Elsevier B. V.出版。
Transforming Growth Factor beta 1 (TGF beta 1) is a crucial cytokine triggering myofibroblastic (MF) differentiation, a process involved in tissue healing as well as in pathologic conditions such as fibrosis and cancer. Together with cell shape modifications, TGF beta 1-mediated differentiation of fibroblasts into myofibroblasts is characteristically associated with the neo-expression of smooth muscle alpha-actin (alpha-SMA), a cytoskeletal protein that enhances their contractile activity. Several cellular differentiation programs have been linked to epigenetic regulation of gene expression, including gene methylation and historic acetylation. Herein, we sought to investigate the role of histone deacetylases (HDAC) in TGF beta 1-induced MY differentiation. We found that TSA, a global inhibitor of class I and class II HDACs, prevented alpha-SMA transcript and protein expression and morphological changes mediated by TGF beta 1 in cultured human skin fibroblasts. In order to identify the HDAC(s) participating in MF differentiation, the impact of specific HDAC silencing (HDAC1 through HDAC8) using RNA interference was investigated in fibroblasts exposed to TGF beta 1. Among the eight HDACs tested, silencing of HDAC4, HDAC6, and HDAC8 expression impaired TGF beta 1-induced alpha-SMA expression. HDAC4 silencing most efficiently abrogated alpha-SMA expression and also prevented TGF beta 1-mediated morphological changes. Forced down-regulation of HDAC4 stimulated the expression of 5'-TG-3'-Interacting Factor (TGIF) and TGIF2 homeoproteins, two known endogenous repressors of the TGF beta signaling pathway, but not of the inhibitory Smad7. Collectively, these data suggest that HDAC4 is an essential epigenetic regulator of MF differentiation and unveil HDAC4 as a potential target for treating MF-related disorders. (C) 2007 Published by Elsevier B.V.