Glucocorticoid receptor coordinates transcription factor-dominated regulatory network in macrophages.
Glucocorticoid receptor coordinates transcription factor-dominated regulatory network in macrophages.
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糖皮质激素受体在巨噬细胞中协调转录因子主导的调节网络。
DOI：
10.1186/1471-2164-15-656
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发表时间：
2014-08-06
期刊：
影响因子：
4.4
通讯作者：
Rogatsky I
中科院分区：
文献类型：
--
作者：
Chinenov Y;Coppo M;Gupte R;Sacta MA;Rogatsky I
由感染或损伤引发的炎症受到糖皮质激素的严格控制，糖皮质激素通过专用的转录因子糖皮质激素受体（GR）发出信号，以调节数百个基因。然而，对GR激活的转录反应的层次结构及其通常非线性动力学的分子基础尚不清楚。我们研究了巨噬细胞中糖皮质激素驱动的早期转录事件，巨噬细胞是一种对促炎和抗炎刺激都有高度反应的细胞类型。在静息和急性脂多糖（LPS）刺激的巨噬细胞中使用全转录组分析，我们发现，早期GR靶基因形成密集的网络，其中大部分控制节点由转录因子代表。几种糖皮质激素反应基因的表达动力学与前馈环（FFL）一致，并与快速GR募集一致。值得注意的是，GR结合位点的基因编码的KLF转录因子家族成员与KLF结合位点共定位。此外，我们的基因表达，转录因子结合和计算数据与GR-KLF 9-KLF 2非相干FFL的存在是一致的。LPS下调基因的分析揭示了惊人的富集多聚化锌指和KRAB结构域的蛋白质结合核酸和抑制转录的异染色质繁殖。这提出了一个有趣的可能性，即炎症性巨噬细胞中染色质可及性的增加是由于负染色质重塑的广泛下调。促炎和抗炎刺激改变大量转录因子和染色质重塑物的表达。通过调节传播初始激素信号的多种转录因子，GR在抗炎反应中充当协调中心。由于几种KLF促进巨噬细胞中的抗炎程序，我们提出GR和KLF在功能上合作以抑制炎症。本文的在线版本（doi：10.1186/1471-2164-15-656）包含补充材料，可供授权用户使用。
Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood. We investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers. Pro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation. The online version of this article (doi:10.1186/1471-2164-15-656) contains supplementary material, which is available to authorized users.
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影响因子：
3.4
作者：
Isserlin, Ruth;Merico, Daniele;Alikhani-Koupaei, Rasoul;Gramolini, Anthony;Bader, Gary D.;Emili, Andrew
通讯作者：
Emili, Andrew
影响因子：
5.8
作者：
Lachmann, Alexander;Xu, Huilei;Ma'ayan, Avi
通讯作者：
Ma'ayan, Avi
DOI：
10.1073/pnas.0910177106
发表时间：
2009-10-27
影响因子：
11.1
作者：
Adelman, Karen;Kennedy, Megan A.;Rogatsky, Inez
通讯作者：
Rogatsky, Inez
影响因子：
21.3
作者：
Jiang, Jianming;Chan, Yun-Shen;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
影响因子：
5.8
作者：
Kino, Tomoshige;Pavlatou, Maria G.;Stratakis, Constantine A.
通讯作者：
Stratakis, Constantine A.