Epigenetic Regulation of Interleukin 6 by Histone Acetylation in Macrophages and Its Role in Paraquat-Induced Pulmonary Fibrosis.
Epigenetic Regulation of Interleukin 6 by Histone Acetylation in Macrophages and Its Role in Paraquat-Induced Pulmonary Fibrosis.
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巨噬细胞中组蛋白乙酰化对白介素 6 的表观遗传调控及其在百草枯诱导的肺纤维化中的作用。
DOI：
10.3389/fimmu.2016.00696
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发表时间：
2016
影响因子：
7.3
通讯作者：
Chen F
中科院分区：
文献类型：
--
作者：
Hu L;Yu Y;Huang H;Fan H;Hu L;Yin C;Li K;Fulton DJ;Chen F
白细胞介素6（IL - 6）的过表达被认为与肺纤维化及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序列不发生改变的情况下基因表达的改变。组蛋白乙酰化对染色质可及性的改变是一种关键的表观遗传机制，可调控多种基因转录。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影响，并探讨表观遗传调控是否在IL - 6的转录调控中起作用。在PQ处理的肺组织和巨噬细胞中，我们发现IL - 6的mRNA和蛋白质表达以时间依赖性和剂量依赖性的方式显著增加。我们的数据表明，PQ诱导的巨噬细胞中IL - 6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）抑制剂可增加IL - 6的表达及其在增强PQ诱导的肺纤维化中的作用，而组蛋白乙酰转移酶（HAT）抑制剂可阻止这种作用。此外，HDAC抑制剂可增强CRISPR - ON转录激活系统（CRISPR - ON）促进IL - 6转录的能力，而HAT抑制剂可阻断这种能力。染色质免疫沉淀实验显示，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在体外和体内均通过表观遗传调控染色质可及性而受到HDAC和HAT的动态调控。
Overexpression of interleukin 6 (IL-6) has been proposed to contribute to pulmonary fibrosis and other fibrotic diseases. However, the regulatory mechanisms and the role of IL-6 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 IL-6 in paraquat (PQ)-induced pulmonary fibrosis and to explore whether the epigenetic regulations may play a role in transcriptional regulation of IL-6. In PQ-treated lungs and macrophages, we found that the mRNA and protein expression of IL-6 was robustly increased in a time-dependent and a dose-dependent manner. Our data demonstrated that PQ-induced IL-6 expression in macrophages plays a central role in pulmonary fibrosis through enhanced epithelial-to-mesenchymal transition (EMT). IL-6 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 IL-6 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 IL-6 promoter regions. In conclusion, IL-6 functioning through EMT in PQ-induced pulmonary fibrosis was regulated dynamically by HDAC and HAT both in vitro and in vivo via epigenetically regulating chromatin accessibility.