Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis
Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis
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DOI：
10.1136/annrheumdis-2012-201615
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发表时间：
2013-04-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Kraemer, Marlene;Dees, Clara;Distler, Joerg H. W.
目的DNA甲基化和组蛋白乙酰化等表观遗传修饰参与了系统性硬化症的发病机制。然而，组蛋白甲基化迄今尚未研究。因此，我们的目的是评估组蛋白H3赖氨酸27（H3 K27 me 3）对成纤维细胞活化和fibrosis.Methods的三甲基化的作用，抑制H3 K27 me 3 3-deazaneplanocin A（DZNep）在培养的成纤维细胞和两个小鼠模型的皮肤纤维化。通过评估真皮增厚、测定羟脯氨酸含量和定量肌成纤维细胞数量来分析纤维化。结果抑制H3 K27 me 3可促进成纤维细胞胶原蛋白的释放，并呈时间和剂量依赖性。用DZNep治疗加重了由博来霉素或由组成性活性转化生长因子β受体I型的过表达诱导的纤维化。此外，单独用DZNep治疗足以诱导纤维化。抑制H3 K27 me 3诱导促纤维化转录因子fra-2在体外和体内的表达。敲低fra-2完全阻止了DZNep.Conclusions的促纤维化作用，这些数据表明H3 Lys 27组蛋白甲基化在纤维化中的新作用。与其他表观遗传修饰如DNA甲基化和组蛋白乙酰化相反，H3 Lys 27组蛋白甲基化通过抑制fra-2的表达在体外和体内充当成纤维细胞活化的负调节剂。
Objectives Epigenetic modifications such as DNA methylation and histone acetylation have been implicated in the pathogenesis of systemic sclerosis. However, histone methylation has not been investigated so far. We therefore aimed to evaluate the role of the trimethylation of histone H3 on lysine 27 (H3K27me3) on fibroblast activation and fibrosis.Methods H3K27me3 was inhibited by 3-deazaneplanocin A (DZNep) in cultured fibroblasts and in two murine models of dermal fibrosis. Fibrosis was analysed by assessment of the dermal thickening, determination of the hydroxyproline content and by quantification of the numbers of myofibroblasts. The expression of fos-related antigen 2 (fra-2) was assessed by real-time PCR, western blot and immunohistochemistry and modulated by siRNA.Results Inhibition of H3K27me3 stimulated the release of collagen in cultured fibroblasts in a time and dose-dependent manner. Treatment with DZNep exacerbated fibrosis induced by bleomycin or by overexpression of a constitutively active transforming growth factor beta receptor type I. Moreover, treatment with DZNep alone was sufficient to induce fibrosis. Inhibition of H3K27me3 induced the expression of the profibrotic transcription factor fra-2 in vitro and in vivo. Knockdown of fra-2 completely prevented the profibrotic effects of DZNep.Conclusions These data demonstrate a novel role of H3 Lys27 histone methylation in fibrosis. In contrast to other epigenetic modifications such as DNA methylation and histone acetylation, H3 Lys27 histone methylation acts as a negative regulator of fibroblast activation in vitro and in vivo by repressing the expression of fra-2.