The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia.
The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia.
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DOI：
10.1007/s00109-013-1090-5
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发表时间：
2014-03
影响因子：
4.7
通讯作者：
Kaminska, Bozena
中科院分区：
文献类型：
--
作者：
Przanowski, Piotr;Dabrowski, Michal;Ellert-Miklaszewska, Aleksandra;Kloss, Michal;Mieczkowski, Jakub;Kaza, Beata;Ronowicz, Anna;Hu, Feng;Piotrowski, Arkadiusz;Kettenmann, Helmut;Komorowski, Jan;Kaminska, Bozena
关键词：
大多数神经系统疾病与小胶质细胞激活引发的慢性炎症有关，小胶质细胞激活产生细胞毒性和炎症因子。信号转导和转录激活因子（STAT）是基因表达的有效调节因子，但特定STAT对炎性基因表达的贡献和脑炎症的STAT依赖性转录网络需要鉴定。在本研究中，我们研究了Stats结合位点的基因组分布以及Stats在脂多糖（LPS）激活的原代小胶质细胞培养物中基因表达中的作用。染色质免疫沉淀启动子微阵列数据和转录组数据的整合揭示了新的STAT靶基因，包括Jmjd 3，Ccl 5，Ezr，Ifih 1，Irf 7，Uba 7和Pim 1。虽然敲低单个Stat对测试基因的表达几乎没有影响，但敲低Stat 1和Stat 3均抑制Jmjd 3和炎症基因的表达。Stat 1和Stat 3对Jmjd 3的转录调控是小胶质细胞启动炎症反应的一种新机制。Jmjd 3对炎症基因表达的影响与其H3 K27 me 3去甲基化酶活性无关。组成性激活的Stat 1和Stat 3的强制表达诱导Jmjd 3、炎症相关基因的表达，以及促炎细胞因子的产生，与脂多糖一样有效。基因集富集和基因功能分析揭示了LPS和Stat 1C + Stat 3C组中与炎症反应相关的类别。我们定义了激活STAT应答LPS的上游途径，并证明了Tlr 4和IL-6以及干扰素-γ信号传导的贡献。我们的研究结果定义了Stat 1和Stat 3的新的直接转录靶点，并强调了它们对炎症基因表达的贡献。基因组Stat占有率和转录组的组合分析揭示了LPS诱导的小胶质细胞中的新型Stat靶基因。Jmjd 3转录因子是Stat 1和Stat 3的新的转录靶点。Stat 1和Stat 3与Jmjd 3协同诱导促炎基因的表达。组成型活性Stat 1和Stat 3完全模拟LPS诱导的炎症基因上调和细胞因子分泌。本文的在线版本（doi：10.1007/s 00109 -013-1090-5）包含补充材料，可供授权用户使用。
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. Combined 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. The online version of this article (doi:10.1007/s00109-013-1090-5) contains supplementary material, which is available to authorized users.
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影响因子：
4.9
作者：
Ivashkiv LB;Hu X
通讯作者：
Hu X
DOI：
10.1084/jem.20030077
发表时间：
2003-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kano A;Wolfgang MJ;Gao Q;Jacoby J;Chai GX;Hansen W;Iwamoto Y;Pober JS;Flavell RA;Fu XY
通讯作者：
Fu XY
影响因子：
5
作者：
Ning, S.;Pagano, J. S.;Barber, G. N.
通讯作者：
Barber, G. N.
影响因子：
3
作者：
Mieczkowski J;Tyburczy ME;Dabrowski M;Pokarowski P
通讯作者：
Pokarowski P
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J