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The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia

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Item Type:Article
Title:The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia
Creators Name:Przanowski, P. and Dabrowski, M. and Ellert-Miklaszewska, A. and Kloss, M. and Mieczkowski, J. and Kaza, B. and Ronowicz, A. and Hu, F. and Piotrowski, A. and Kettenmann, H. and Komorowski, J. and Kaminska, B.
Abstract:Most neurological diseases are associated with chronic inflammation initiated by the activation of microglia, which produce cytotoxic and inflammatory factors. Signal transducers and activators of transcription (STATs) are potent regulators of gene expression but contribution of particular STAT to inflammatory gene expression and STAT-dependent transcriptional networks underlying brain inflammation need to be identified. In the present study, we investigated the genomic distribution of Stat binding sites and the role of Stats in the gene expression in lipopolysaccharide (LPS)-activated primary microglial cultures. Integration of chromatin immunoprecipitation-promoter microarray data and transcriptome data revealed novel Stat-target genes including Jmjd3, Ccl5, Ezr, Ifih1, Irf7, Uba7, and Pim1. While knockdown of individual Stat had little effect on the expression of tested genes, knockdown of both Stat1 and Stat3 inhibited the expression of Jmjd3 and inflammatory genes. Transcriptional regulation of Jmjd3 by Stat1 and Stat3 is a novel mechanism crucial for launching inflammatory responses in microglia. The effects of Jmjd3 on inflammatory gene expression were independent of its H3K27me3 demethylase activity. Forced expression of constitutively activated Stat1 and Stat3 induced the expression of Jmjd3, inflammation-related genes, and the production of pro-inflammatory cytokines as potently as lipopolysacharide. Gene set enrichment and gene function analysis revealed categories linked to the inflammatory response in LPS and Stat1C + Stat3C groups. We defined upstream pathways that activate STATs in response to LPS and demonstrated contribution of Tlr4 and Il-6 and interferon-{gamma} signaling. Our findings define novel direct transcriptional targets of Stat1 and Stat3 and highlight their contribution to inflammatory gene expression.
Keywords:Inflammation, Signal Transducers and Activators of Transcription, ChIP-chip, Jmjd3, H3K27me3 Histone Demethylase, Brain Macrophages, Animals, Rats
Source:Journal of Molecular Medicine
ISSN:0946-2716
Publisher:Springer (Germany)
Volume:92
Number:3
Page Range:239-254
Date:March 2014
Official Publication:https://doi.org/10.1007/s00109-013-1090-5
PubMed:View item in PubMed

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