The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis
The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis
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DOI：
10.1136/annrheumdis-2017-211501
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发表时间：
2018-01-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
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作者：
Bergmann, Christina;Brandt, Amelie;Distler, Joerg H. W.
目的 即使没有外源刺激，系统性硬化症 (SSc) 成纤维细胞仍保持激活状态。表观遗传改变被认为在这种内源性激活中发挥了作用。组蛋白 H3 在赖氨酸 27 上的三甲基化 (H3K27me3) 由包含 Jumonji 结构域的蛋白 3 (JMJD3) 和 X 染色体 (UTX) 上普遍转录的四肽重复序列以治疗靶向方式调节。本研究的目的是探索H3K27me3去甲基酶作为治疗纤维化的潜在靶点。方法通过小干扰RNA介导的敲低和GSKJ4的药理抑制来灭活JMJD3。在培养的成纤维细胞以及博莱霉素诱导和拓扑异构酶 I (topoI) 诱导的纤维化小鼠模型中分析了 JMJD3 靶向失活的影响。通过 ChIP 分析 FRA2 启动子处的 H3K27me3。 结果 在 SSc 皮肤的成纤维细胞和实验性纤维化中，JMJD3 的表达以转化生长因子 β (TGF β) 依赖性方式增加，但 UTX 的表达不增加。 JMJD3 失活可逆转 SSc 成纤维细胞中激活的成纤维细胞表型，并阻止 TGF β 激活健康真皮成纤维细胞。在耐受良好的剂量下，JMJD3 的药理学抑制可改善博来霉素诱导的和拓扑异构酶 I 诱导的纤维化。 JMJD3 以 FRA2 依赖性方式调节成纤维细胞活化：JMJD3 失活通过诱导 FRA2 启动子处 H3K27me3 的积累来减少 FRA2 的表达。此外，FRA2 敲低后，JMJD3 抑制的抗纤维化作用降低。 结论 我们提出了 SSc 中 JMJD3 失调的第一个证据。 JMJD3 通过调节 FRA2 启动子处的 H3K27me3 水平来调节成纤维细胞活化。 JMJD3 的靶向抑制限制了 SSc 成纤维细胞的异常激活，并在两种小鼠模型中发挥抗纤维化作用。
Objectives Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.Methods JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.Results The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGF beta)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGF beta. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.Conclusion We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.