Title: MKL1 mediates TNF-α induced pro-inflammatory transcription by bridging the crosstalk between BRG1 and WDR5


Authors: Wenping Xu1, Quanyi Zhao2, Min Wu2, Mingming Fang1, Yong Xu3


Institutions: 1Department of Medicine, Jiangsu Jiankang Vocational College, Nanjing, Jiangsu 211800, China; 2Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; 3Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, Jiangsu 211166, China.


Abstract: 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.


Keywords: MKL1, WDR5, BRG1, macrophage, transcriptional regulation


Full Text: JBR-2017-0025.pdf


J biomed Res published on 30 July 2017, doi:10.7555/JBR.32.20170025