Xu Wenping, Zhao Quanyi, Wu Min, Fang Mingming, Xu Yong
Department of Medicine, Jiangsu Jiankang Vocational College, Nanjing, Jiangsu 211800, China.
Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
J Biomed Res. 2019 Jun 4;33(3):164-172. doi: 10.7555/JBR.32.20170025.
Tumor necrosis factor alpha (TNF-α) is a cytokine that can potently stimulate the synthesis of a range of pro-inflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) is associated with a histone H3K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of pro-inflammatory genes. In contrast, silencing of WDR5 attenuates TNF-α induced production of pro-inflammatory mediators and erases the H3K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-α induced pro-inflammatory transcription in macrophages.
肿瘤坏死因子α（TNF-α）是一种细胞因子，能够有力地刺激巨噬细胞中一系列促炎介质的合成。然而，其潜在的表观遗传机制尚未得到充分研究。在此我们报告，转录调节因子巨核细胞白血病1（MKL1）与组蛋白H3K4甲基转移酶活性相关。再染色质免疫沉淀（Re-ChIP）分析表明，在经TNF-α处理的巨噬细胞中，MKL1与COMPASS复合物中负责H3K4甲基化的成分WDR5相互作用并将其招募至促炎基因的启动子区域。WDR5增强了MKL1刺激促炎基因启动子活性的能力。相反，WDR5的沉默减弱了TNF-α诱导的促炎介质产生，并消除了基因启动子上的H3K4甲基化。有趣的是，染色质重塑蛋白BRG1也通过与WDR5相互作用，在维持MKL1靶启动子上的H3K4甲基化方面发挥重要作用。MKL1的敲低破坏了BRG1与WDR5之间的相互作用。总之，我们的数据表明MKL1在调节BRG1与WDR5之间的串扰以激活TNF-α诱导的巨噬细胞促炎转录中发挥作用。
