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

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-γ signaling. Our findings define novel direct transcriptional targets of Stat1 and Stat3 and highlight their contribution to inflammatory gene expression.Key MessageCombined analysis of genomic Stat occupancy and transcriptome revealed novel Stat target genes in LPS-induced microglia.Jmjd3 transcription factor is a novel transcriptional target of Stat1 and Stat3.Stat1 and Stat3 cooperate with Jmjd3 to induce the expression of pro-inflammatory genes.Constitutively active Stat1 and Stat3 fully mimic the LPS-induced upregulation of inflammatory genes and secretion of cytokines.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-013-1090-5) contains supplementary material, which is available to authorized users.

RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

“…4H). Similarly, the histone demethylase JMJD3 is a HIF target gene product that regulates IL6 expression (40). Paclitaxel treatment increased JMJD3 mRNA expression and coadministration of digoxin or acriflavine blocked the effect of paclitaxel (Fig.…”

Linking STAT and TLR signaling in microglia: a new role for the histone demethylase Jmjd3

“…Upon homo-and heterodimerization, STATs would also drive gene transcription (6). Based on the findings of Przanowski et al [6], Jmjd3 (7) would be induced via NFκB-dependent as well as STAT-dependent pathways (3,6) while serving itself as a transcription factor for the induction of proinflammatory cyto-and chemokines (8). Interestingly, this transcription factor role does not require the histone demethylase activity, which has been assigned to Jmjd3 as its primary function thus far.…”

“…The work of Przanowski and collaborators [6] combines both kinds of surprises by linking Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling elements closely to the world of Toll-like receptors (TLRs). Not enough, an enzyme known for removing methyl groups from lysine 27 residues in H3 histones, the H3K27me3 demethylase Jmjd3, appears to be a key element in this cooperation-yet not by its enzymatic activity but as a transcription factor.…”

“…Przanowski and coworkers identified previously unknown STAT target genes in TLR4 agonist-stimulated microglia [6]. TLR4 is best known for the binding and signaling of lipopolysaccharide (LPS), a major cell wall component of gramnegative bacteria and a prototypical PAMP.…”

“…Cytokines, like IL-6, or IFNβ could thus activate receptors linked to JAK family members, which in turn activate (i.e., phosphorylate) STAT proteins (5). Upon homo-and heterodimerization, STATs would also drive gene transcription (6). Based on the findings of Przanowski et al [6], Jmjd3 (7) would be induced via NFκB-dependent as well as STAT-dependent pathways (3,6) while serving itself as a transcription factor for the induction of proinflammatory cyto-and chemokines (8).…”