T-bet's ability to regulate individual target genes requires the conserved T-box domain to recruit histone methyltransferase activity and a separate family member-specific transactivation domain
T-bet's ability to regulate individual target genes requires the conserved T-box domain to recruit histone methyltransferase activity and a separate family member-specific transactivation domain
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DOI：
10.1128/mcb.01615-07
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发表时间：
2007-12-01
影响因子：
5.3
通讯作者：
Weinmann, Amy S.
中科院分区：
文献类型：
--
作者：
Lewis, Megan D.;Miller, Sara A.;Weinmann, Amy S.
适当的细胞分化和特化依赖于关键发育转录因子精确建立基因表达模式的能力。这些转录因子通常调节表观遗传事件。然而，目前还不清楚这是否是唯一的作用，他们在功能上调节发育基因表达途径，或者他们是否也参与下游的反式激活事件在同一个启动子。T-box转录因子家族在许多发育系统中的细胞特异性事件中是重要的，并且确定该家族调节基因表达网络的分子机制值得关注。在这里，我们研究的机制，T-bet，在免疫系统中的一个关键的T-box蛋白，影响转录。T-bet对于在CXCR 3和IFN-γ启动子处诱导允许的组蛋白H3-K4二甲基修饰是必要且足够的。T-bet结构-功能分析表明，保守的T-box结构域，具有一个小的C-末端部分，需要招募组蛋白甲基转移酶活性的启动子。有趣的是，这种功能在T-box家族中是保守的，并且是诱导转录所必需的，但不是充分的，还需要独立的反式激活活性。两个可分离的功能活动的要求可能最终有助于严格的作用，T盒蛋白在建立特定的发育基因表达途径。
Appropriate cellular differentiation and specification rely upon the ability of key developmental transcription factors to precisely establish gene expression patterns. These transcription factors often regulate epigenetic events. However, it has been unclear whether this is the only role that they play in functionally regulating developmental gene expression pathways or whether they also participate in downstream transactivation events at the same promoter. The T-box transcription factor family is important in cellular specification events in many developmental systems, and determining the molecular mechanisms by which this family regulates gene expression networks warrants attention. Here, we examine the mechanism by which T-bet, a critical T-box protein in the immune system, influences transcription. T-bet is both necessary and sufficient to induce permissive histone H3-K4 dimethyl modifications at the CXCR3 and IFN-gamma promoters. A T-bet structure-function analysis revealed that the conserved T-box domain, with a small C-terminal portion, is required for recruiting histone methyltransferase activity to promoters. Interestingly, this function is conserved in the T-box family and is necessary, but not sufficient, to induce transcription, with an independent transactivation activity also required. The requirement for two separable functional activities may ultimately contribute to the stringent role for T-box proteins in establishing specific developmental gene expression pathways.