Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Scleroderma Program, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3695-3702. doi: 10.1073/pnas.1813006116. Epub 2019 Feb 12.
Scleroderma (SSc) is a complex disease that involves activation of the immune system, vascular complications, and tissue fibrosis. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) mediates trimethylation of lysine 27 of histone 3 (H3K27me3), which acts as a repressive epigenetic mark. Both EZH2 and H3K27me3 were elevated in SSc dermal fibroblasts and endothelial cells compared with healthy controls. EZH2 inhibitor DZNep halted fibrosis both in vitro and in vivo. In SSc fibroblasts, DZNep dose-dependently reduced the expression of profibrotic genes and inhibited migratory activity of SSc fibroblasts. We show that epigenetic dysregulation and overexpression of LRRC16A explains EZH2-mediated fibroblast migration in SSc. In endothelial cells, inhibition of EZH2 restored normal angiogenesis in SSc via activating the Notch pathway, specifically by up-regulating the Notch ligand DLL4. Our results demonstrate that overexpression of EZH2 in SSc fibroblasts and endothelial cells is profibrotic and antiangiogenic. Targeting EZH2 or EZH2-regulated genes might be of therapeutic potential in SSc.
硬皮病（SSc）是一种复杂的疾病，涉及免疫系统激活、血管并发症和组织纤维化。组蛋白甲基转移酶增强子的锌指蛋白 2（EZH2）介导组蛋白 3（H3K27me3）赖氨酸 27 的三甲基化，作为一种抑制性表观遗传标记。与健康对照组相比，EZH2 和 H3K27me3 在 SSc 皮肤成纤维细胞和内皮细胞中均升高。EZH2 抑制剂 DZNep 在体外和体内均阻止纤维化。在 SSc 成纤维细胞中，DZNep 呈剂量依赖性降低致纤维化基因的表达，并抑制 SSc 成纤维细胞的迁移活性。我们表明，表观遗传失调和 LRRC16A 的过度表达解释了 EZH2 介导的 SSc 成纤维细胞迁移。在内皮细胞中，通过激活 Notch 通路，特别是通过上调 Notch 配体 DLL4，抑制 EZH2 恢复了 SSc 中的正常血管生成。我们的结果表明，EZH2 在 SSc 成纤维细胞和内皮细胞中的过度表达是促纤维化和抗血管生成的。靶向 EZH2 或 EZH2 调节的基因可能在 SSc 中有治疗潜力。
