Key Laboratory of Targeted Intervention of Cardiovascular Disease and Innovative Collaboration Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China.
Biochem Biophys Res Commun. 2019 Jun 18;514(1):16-23. doi: 10.1016/j.bbrc.2019.04.105. Epub 2019 Apr 20.
One of the hallmark events during liver fibrosis is the transition of quiescent hepatic stellate cells (HSC) into activated myofibroblasts, which are responsible for the production and deposition of pro-fibrogenic proteins. The epigenetic mechanism underlying HSC trans-differentiation is not fully understood. In the present study we investigated the contribution of histone H3K9 demethylase KDM4 in this process. We report that expression levels of KDM4 were down-regulated during HSC activation paralleling the up-regulation of alpha smooth muscle cell actin (Acta2), a marker of mature myofibroblast. Furthermore, HSCs isolated from mice induced to develop liver fibrosis exhibit lowered KDM4 expression compared to the control mice. In accordance, KDM4 depletion with siRNA accelerated HSC activation. Of interest, the loss of KDM4 was mirrored by the repression of miR-29, an antagonist of liver fibrosis, during HSC activation both in vitro and in vivo. KDM4 knockdown resulted in the down-regulation of miR-29 expression. Mechanistically, the sequence-specific transcription factor SREBP2 interacted with KDM4 to activate miR-29 transcription. In conclusion, our data delineate a novel epigenetic mechanism underlying HSC activation. Targeting this axis may yield potential therapeutics against liver fibrosis.
肝纤维化过程中的一个标志性事件是静止的肝星状细胞（HSC）向激活的肌成纤维细胞的转化，肌成纤维细胞负责产生和沉积促纤维化蛋白。HSC 转分化的表观遗传机制尚不完全清楚。在本研究中，我们研究了组蛋白 H3K9 去甲基酶 KDM4 在这个过程中的作用。我们报告说，KDM4 的表达水平在 HSC 激活过程中下调，与成熟肌成纤维细胞的标志物α平滑肌肌动蛋白（Acta2）的上调平行。此外，与对照组小鼠相比，诱导发生肝纤维化的小鼠中分离出的 HSCs 表现出较低的 KDM4 表达。与此一致，用 siRNA 耗尽 KDM4 可加速 HSC 激活。有趣的是，在体外和体内，HSC 激活过程中，KDM4 的丢失与 miR-29 的抑制相吻合，miR-29 是肝纤维化的拮抗剂。KDM4 敲低导致 miR-29 表达下调。从机制上讲，序列特异性转录因子 SREBP2 与 KDM4 相互作用，激活 miR-29 转录。总之，我们的数据描绘了 HSC 激活的一种新的表观遗传机制。针对该轴可能为肝纤维化提供潜在的治疗方法。
