A double-bromo domain protein, FSH-S, activates the homeotic gene Ultrabithorax through a critical promoter-proximal region
A double-bromo domain protein, FSH-S, activates the homeotic gene Ultrabithorax through a critical promoter-proximal region
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DOI：
10.1128/mcb.00692-07
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Huang, Der-Hwa
中科院分区：
文献类型：
--
作者：
Chang, Yuh-Long;King, Balas;Huang, Der-Hwa
超过12种三胸蛋白（trxG）参与果蝇HOX基因的激活。它们是如何协调地整合来自远距离增强子的信号的，目前还不完全清楚。雌性不育(1)同源基因（fs(1)h）是trxG基因之一，对超胸腺（Ubx）的激活至关重要。我们发现fs(I)h编码的两个双溴结构域蛋白中的一个在Ubx近端启动子中起重要作用。首先，小异构体FSH-S过表达，而大异构体FSH-S过表达，可诱导HOX基因异位表达，导致机体畸形。其次，FSH-S可以通过一个关键的近端区域以溴域依赖的方式刺激培养细胞中的Ubx启动子。第三，纯化的FSH-S可以特异性结合该区域内的基序，该区域以前被称为ZESTE位点。利用含有修饰的Ubx近端启动子和染色质免疫沉淀的转基因胚胎确定了FSH-S的生理相关性。此外，我们发现FSH-S参与了自身和其他调节因子的磷酸化。我们认为FSH-S是调节远端增强子远程效应的调控回路的关键组成部分。
More than a dozen trithorax group (trxG) proteins are involved in activation of Drosophila HOX genes. How they act coordinately to integrate signals from distantly located enhancers is not fully understood. The female sterile (1) homeotic (fs(1)h) gene is one of the trxG genes that is most critical for Ultrabithorax (Ubx) activation. We show that one of the two double-bromodomain proteins encoded by fs(I)h acts as an essential factor in the Ubx proximal promoter. First, overexpression of the small isoform FSH-S, but not the larger one, can induce ectopic expression of HOX genes and cause body malformation. Second, FSH-S can stimulate Ubx promoter in cultured cells through a critical proximal region in a bromodomain-dependent manner. Third, purified FSH-S can bind specifically to a motif within this region that was previously known as the ZESTE site. The physiological relevance of FSH-S is ascertained using transgenic embryos containing a modified Ubx proximal promoter and chromatin immunoprecipitation. In addition, we show that FSH-S is involved in phosphorylation of itself and other regulatory factors. We suggest that FSH-S acts as a critical component of a regulatory circuitry mediating long-range effects of distant enhancers.