Journal
BIOCHEMICAL PHARMACOLOGY
Volume 137, Issue -, Pages 61-80Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2017.04.016
Keywords
Enhancer of zeste homolog 2 (EZH2); IRF1, 8/STAT1 pathway; Neuroinflammation; RNA sequencing
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Funding
- Korean government (MSIP) [2016R1D1A1B04934970, 2011-0030049, 2017R1A2B4012905]
- National Research Foundation of Korea (NRF)
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Multiple studies have documented that Enhancer of zeste homolog 2 (EZH2) could play a role in inflammation and a wide range of malignancies; however, the underlying mechanisms remain largely unaddressed. Microglial activation is a key process in the production and release of numerous pro inflammatory mediators that play important roles in inflammation and neurodegeneration in the central nervous system (CNS). Therefore, our aim was to investigate whether inhibition of EZH2 with the selective small molecule inhibitor EPZ-6438 protects against neonatal microglial activation. First, in mouse primary microglial cells and a microglial cell line, we found that LPS can rapidly increase EZH2 mRNA level and we subsequently performed gene expression profiling and constructed networks in resting, EPZ-6438-treated, LPS-treated and LPS + EPZ-6438-treated primary microglial cells and a microglial cell line using transcriptome RNA sequencing and bioinformatics analyses. By examining the RNA sequencing, we identified EPZ-6438 target genes and co-regulated modules that were critical for inflammation. We also identified unexpected relationships between the inducible transcription factors (TFs), motif strength, and the transcription of key inflammatory mediators. Furthermore, we showed that EPZ-6438 controls important inflammatory gene targets by modulating interferon regulatory factor (IRF) 1, IRF8, and signal transducer and activator of transcription (STAT) 1 levels at their promoter sites. Our unprecedented findings demonstrate that pharmacological interventions built upon EZH2 inhibition by EPZ-6438 could be a useful therapeutic approach for the treatment of neuroinflammatory diseases associated with microglial activation. (C) 2017 Elsevier Inc. All rights reserved.
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