Mechanism of action of a distal NF-κB-dependent enhancer
Mechanism of action of a distal NF-κB-dependent enhancer
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DOI：
10.1128/mcb.00271-06
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Boss, Jeremy M.
中科院分区：
文献类型：
--
作者：
Teferedegne, Belete;Green, Myesha R.;Boss, Jeremy M.
单核细胞趋化蛋白1基因（MCP-1）受TNF通过NF-κ B依赖性远端增强子和Sp1依赖性启动子近端调控区调控。在沉默状态下，只有远端调控区可接近转录因子。在被肿瘤坏死因子激活后，NF-κ B与远端调节区结合并募集CBP和p300。CBP和p300募集导致特异性组蛋白修饰，最终使Sp1与近端调控区结合。在此过程中，远端和近端调节区之间发生直接相互作用。这种相互作用需要Sp1、NF-κ B、CBP和p300。CBP/p300介导的组蛋白修饰增强了辅激活因子CARM 1与远端调控区的结合。CARM 1是MCP-1表达所必需的，而远端-近端区域相互作用不需要CARM 1，这表明它在下游激活事件中起作用。结果描述了一种模型，其中远端增强子与启动子近端区域的分离允许两个独立的染色质状态存在，防止启动子处的不适当基因激活，同时允许通过远端调控区快速诱导。
The monocyte chemoattractant protein 1 gene (MCP-1) is regulated by TNF through an NF-kappa B-dependent distal enhancer and an Sp1-dependent promoter-proximal regulatory region. In the silent state, only the distal regulatory region is accessible to transcription factors. Upon activation by tumor necrosis factor, NF-kappa B binds to the distal regulatory region and recruits CBP and p300. CBP and p300 recruitment led to specific histone modifications that ultimately enabled the binding of Sp1 to the proximal regulatory region. During this process, a direct interaction between the distal and proximal regulatory regions occurred. Sp1, NF-kappa B, CBP, and p300 were required for this interaction. CBP/p300-mediated histone modifications enhanced the binding of the coactivator CARM1 to the distal regulatory region. CARM1, which is necessary for MCP-1 expression, was not required for distal-proximal region interactions, suggesting that it plays a later downstream activation event. The results describe a model in which the separation of the distal enhancer from the promoter-proximal region allows for two independent chromatin states to exist, preventing inappropriate gene activation at the promoter while at the same time allowing rapid induction through the distal regulatory region.