TGF-β-mediated Foxp3 gene expression is cooperatively regulated by Stat5, Creb, and AP-1 through CNS2.
TGF-β-mediated Foxp3 gene expression is cooperatively regulated by Stat5, Creb, and AP-1 through CNS2.
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DOI：
10.4049/jimmunol.1301892
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Tone M
中科院分区：
文献类型：
--
作者：
Ogawa C;Tone Y;Tsuda M;Peter C;Waldmann H;Tone M
Foxp3 在调节性 T 细胞 (Treg) 的发育和功能中发挥着重要作用。 Foxp3 基因表达的诱导和维持均由多个调控区域控制，包括保守非编码序列 (CNS) 中的两个增强子。 CNS1 中增强子 1 的功能已明确，而 CNS2 中增强子 2 的功能仍不清楚。尽管 CNS2 含有增强子活性，但该区域的甲基化 CpG 序列会阻止 Foxp3− T 细胞中的 Foxp3 基因表达。然而，这些序列在 Foxp3+ Treg 中去甲基化的机制尚不清楚。为了研究CNS2的作用，我们在没有甲基化的情况下通过荧光素酶报告基因测定确定了Enhancer 2核心序列以排除抑制作用，并表明转录因子AP-1、Stat5和Creb协同调节Enhancer 2活性。然后我们确定了每个转录因子的甲基化敏感性。发现 AP-1 对甲基化敏感，正如之前针对 Creb 所描述的那样。然而，即使 Stat5 在 CNS2 中的结合位点被甲基化，它仍然具有活性。 Stat5 与增强子 2 的结合发生较早，并且在 Treg 诱导过程中先于 AP-1 和 Creb。此外，Stat5 激活本身依赖于 TGF-β 信号传导，通过 Smad3 介导的 Socs3 表达阻断。这些发现表明 Stat5 是 iTreg 诱导过程中打开 CNS2 区域的关键调节因子，而 AP-1 和 Creb 则维持增强子 2 的活性。
Foxp3 plays an important role in the development and the function of regulatory T cells (Treg). Both the induction and maintenance of Foxp3 gene expression are controlled by several regulatory regions including two enhancers in the conserved noncoding sequences (CNS). The functions of Enhancer 1 in CNS1 are well established, whereas those of Enhancer 2 in CNS2 remain unclear. Although CNS2 contains enhancer activity, methylated CpG sequences in this region prevent Foxp3 gene expression in Foxp3− T cells. These sequences are however demethylated in Foxp3+ Treg by mechanisms as yet unknown. To investigate the role of CNS2, we have determined the Enhancer 2 core sequence by luciferase reporter assays in the absence of methylation to exclude the inhibitory effect, and shown that transcription factors AP-1, Stat5 and Creb cooperate in regulating Enhancer 2 activity. We have then determined the methylation sensitivity of each of the transcription factors. AP-1 was found to be methylation sensitive as has previously been described for Creb. However, Stat5 was active even when its binding site in CNS2 was methylated. Stat5 binding to Enhancer 2 occurred early, and preceded that of AP-1 and Creb during Treg induction. In addition, Stat5 activation is itself dependent on TGF-β signaling through Smad3 mediated blockade of Socs3 expression. These findings suggest that Stat5 is a key regulator for opening up the CNS2 region during iTreg induction, while AP-1 and Creb maintain Enhancer 2 activity.
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影响因子：
4.4
作者：
Burchill, Matthew A.;Yang, Jianying;Farrar, Michael A.
通讯作者：
Farrar, Michael A.
DOI：
10.1073/pnas.88.9.3720
发表时间：
1991-05-01
影响因子：
11.1
作者：
HAI, T;CURRAN, T
通讯作者：
CURRAN, T
GATA3驱动的Th2响应抑制TGF-BETA1诱导的FOXP3表达和调节T细胞的形成。
影响因子：
9.8
作者：
Mantel PY;Kuipers H;Boyman O;Rhyner C;Ouaked N;Rückert B;Karagiannidis C;Lambrecht BN;Hendriks RW;Crameri R;Akdis CA;Blaser K;Schmidt-Weber CB
通讯作者：
Schmidt-Weber CB
影响因子：
29.7
作者：
Josefowicz SZ;Lu LF;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
4.4
作者：
Ouaked, Nadia;Mantel, Pierre-Yves;Schmidt-Weber, Carsten B.
通讯作者：
Schmidt-Weber, Carsten B.