Hu Lingli, Yu Yanfang, Huang Huijie, Fan Hanting, Hu Li, Yin Caiyong, Li Kai, Fulton David J R, Chen Feng
Department of Forensic Medicine, Nanjing Medical University , Nanjing , China.
Vascular Biology Center, Augusta University, Augusta, GA, USA; Department of Pharmacology, Augusta University, Augusta, GA, USA.
Front Immunol. 2017 Jan 30;7:696. doi: 10.3389/fimmu.2016.00696. eCollection 2016.
Overexpression of interleukin 6 () has been proposed to contribute to pulmonary fibrosis and other fibrotic diseases. However, the regulatory mechanisms and the role of in fibrosis remain poorly understood. Epigenetics refers to alterations of gene expression without changes in the DNA sequence. Alternation of chromatin accessibility by histone acetylation acts as a critical epigenetic mechanism to regulate various gene transcriptions. The goal of this study was to determine the impact of in paraquat (PQ)-induced pulmonary fibrosis and to explore whether the epigenetic regulations may play a role in transcriptional regulation of . In PQ-treated lungs and macrophages, we found that the mRNA and protein expression of was robustly increased in a time-dependent and a dose-dependent manner. Our data demonstrated that PQ-induced expression in macrophages plays a central role in pulmonary fibrosis through enhanced epithelial-to-mesenchymal transition (EMT). expression and its role to enhance PQ-induced pulmonary fibrosis were increased by histone deacetylase (HDAC) inhibition and prevented by histone acetyltransferase (HAT) inhibition. In addition, the ability of CRISPR-ON transcription activation system (CRISPR-ON) to promote transcription of was enhanced by HDAC inhibitor and blocked by HAT inhibitor. Chromatin immunoprecipitation experiments revealed that HDAC inhibitor increased histones activation marks H3K4me3 and H3K9ac at promoter regions. In conclusion, functioning through EMT in PQ-induced pulmonary fibrosis was regulated dynamically by HDAC and HAT both and epigenetically regulating chromatin accessibility.
白细胞介素6（IL-6）的过表达被认为与肺纤维化和其他纤维化疾病有关。然而，其调控机制以及IL-6在纤维化中的作用仍知之甚少。表观遗传学是指在DNA序列不变的情况下基因表达的改变。组蛋白乙酰化引起的染色质可及性改变是调节各种基因转录的关键表观遗传机制。本研究的目的是确定IL-6在百草枯（PQ）诱导的肺纤维化中的作用，并探讨表观遗传调控是否可能在IL-6的转录调控中发挥作用。在PQ处理的肺组织和巨噬细胞中，我们发现IL-6的mRNA和蛋白表达呈时间和剂量依赖性显著增加。我们的数据表明，PQ诱导巨噬细胞中IL-6的表达通过增强上皮-间质转化（EMT）在肺纤维化中起核心作用。组蛋白去乙酰化酶（HDAC）抑制可增加IL-6的表达及其增强PQ诱导的肺纤维化的作用，而组蛋白乙酰转移酶（HAT）抑制则可阻止这种作用。此外，CRISPR-ON转录激活系统促进IL-6转录的能力被HDAC抑制剂增强，被HAT抑制剂阻断。染色质免疫沉淀实验表明，HDAC抑制剂增加了IL-6启动子区域的组蛋白激活标记H3K4me3和H3K9ac。总之，在PQ诱导的肺纤维化中通过EMT发挥作用的IL-6受到HDAC和HAT的动态调控，二者均通过表观遗传方式调节染色质可及性。
