GSE94144: Selective inhibition of EZH2 by a small molecule inhibitor regulates microglia gene expression essential for inflammation
Bulk RNA sequencing
Impressive studies have been well documented that Enhancer of zeste homolog 2 (EZH2) could have a role in inflammation as well as 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 plays an important role in central nervous system (CNS) inflammation and neurodegeneration. Therefore, our aim was to investigate whether inhibition of EZH2 with selective small molecule inhibitors EPZ-6438 protects against neonatal microglia activation. First, we find that BV-2 microglia, LPS can rapidly increase EZH2 mRNA level and subsequently we performed gene expression profiles and networks in resting, EPZ-6438, LPS and LPS+EPZ-6438 challenged BV-2 microglia by transcriptome RNA sequencing and bioinformatic analyses. By examining RNA sequencing we identified EPZ-6438 target genes and co-regulated modules that were critical in 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 genes targets by modulating interferon regulatory factor (IRF) 1, IRF8, Signal transducer and activator of transcription (STAT) 1 levels at their promoter site. Our unprecedented findings demonstrate that pharmacological interventions built upon EZH2 inhibition by EPZ-6438 could be a useful therapeutic application in neuroinflammatory diseases associated with microglia activation. SOURCE: Young Gyu Chai (email@example.com) - Hanyang Univ.