Antisilencing: Myelin proteolipid protein gene expression in oligodendrocytes is regulated via derepression
Antisilencing: Myelin proteolipid protein gene expression in oligodendrocytes is regulated via derepression
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DOI：
10.1046/j.1471-4159.1999.0722227.x
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发表时间：
1999-06-01
影响因子：
4.7
通讯作者：
Wight, PA
中科院分区：
文献类型：
--
作者：
Dobretsova, A;Wight, PA
到目前为止，抗沉默或抗抑制元件只针对少数真核基因进行了描述，并通过它们本身不能增强基因表达，而是推翻了通过负转录调节元件介导的抑制作用而被鉴定。在这里，我们报告了第一例神经特异性基因-髓鞘蛋白脂蛋白(PLP)基因(PLP)的抗沉默。PLP是中枢神经系统髓鞘中含量最丰富的蛋白质，在少突胶质细胞中合成，其表达受发育调控。此前，我们已经证明，PLP-LacZ转基因(包括Pip内含子1的完整序列)在小鼠中受到调控，其方式与内源性Pip基因的空间和时间表达一致。在本报告中，我们通过使用不同的PLP-LacZ缺失结构的转染分析证明，Pip内含子1 DNA包含多种共同调节少突胶质细胞中Pip基因表达的元件。其中一个调控元件起到了抗沉默元件的作用，它的作用超过了位于Pip内含子1 DNA其他地方的至少两个负调控元件所介导的抑制。抗沉默的机制似乎很复杂，因为介导这一功能的基因内区特异性地结合了多个核因子。
Antisilencer or antirepressor elements have been described, thus far, for only a few eukaryotic genes and were identified by their ability not to augment gene expression per se but to override repression mediated via negative transcription regulatory elements. Here we report the first case of antisilencing for a neural-specific gene, the myelin proteolipid protein (PLP) gene (Plp). PLP is the most abundant protein found in CNS myelin, The protein is synthesized in oligodendrocytes, and its expression is regulated developmentally. Previously we have shown that a PLP-lacZ transgene (which includes the entire sequence for Pip intron 1) is regulated in mice, in a manner consistent with the spatial and temporal expression of the endogenous Pip gene. In the present report, we demonstrate by transfection analyses, using various PLP-lacZ deletion constructs, that Pip intron 1 DNA contains multiple elements that collectively regulate Pip gene expression in oligodendrocytes. One of these regulatory elements functions as an antisilencer element, which acts to override repression mediated by at least two negative regulatory elements located elsewhere within Pip intron 1 DNA. The mechanism for antisilencing appears to be complex as the intragenic region that mediates this function binds multiple nuclear factors specifically.