Regulatory elements required for the activation and repression of the protocadherin-α gene cluster
Regulatory elements required for the activation and repression of the protocadherin-α gene cluster
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DOI：
10.1073/pnas.1114357108
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发表时间：
2011-10-11
影响因子：
11.1
通讯作者：
Maniatis, Tom
中科院分区：
文献类型：
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作者：
Kehayova, Polina;Monahan, Kevin;Maniatis, Tom
小鼠原钙粘蛋白（Pcdh）-α，β和γ基因簇编码超过50种蛋白质亚型，其组合表达在大脑中产生巨大的单细胞多样性。目前，表达这种多样性的机制尚不清楚。在这里，我们表明，两个转录增强子元件，HS 5 -1和HS 7，在小鼠Pcdh α基因表达中发挥关键作用。我们发现，HS 5 -1元件的功能作为一个增强子在神经元和非神经元细胞的沉默。增强子活性与锌指DNA结合蛋白CTCF与靶启动子的结合相关，沉默子活性需要非神经元细胞中REST/NRSF阻遏物复合物的结合。因此，HS 5 -1元件作为神经元特异性增强子和非神经元细胞阻遏物发挥功能。相比之下，HS 7元件作为Pcdh α簇范围的转录增强子元件起作用。这些研究揭示了产生单细胞Pcdh多样性所需的调控元件的复杂组织。
The mouse protocadherin (Pcdh) -alpha, -beta, and -gamma gene clusters encode more than 50 protein isoforms, the combinatorial expression of which generates vast single-cell diversity in the brain. At present, the mechanisms by which this diversity is expressed are not understood. Here we show that two transcriptional enhancer elements, HS5-1 and HS7, play a critical role in Pcdh alpha gene expression in mice. We show that the HS5-1 element functions as an enhancer in neurons and a silencer in nonneuronal cells. The enhancer activity correlates with the binding of zinc finger DNA binding protein CTCF to the target promoters, and the silencer activity requires the binding of the REST/NRSF repressor complex in nonneuronal cells. Thus, the HS5-1 element functions as a neuron-specific enhancer and nonneuronal cell repressor. In contrast, the HS7 element functions as a Pcdh alpha cluster-wide transcription enhancer element. These studies reveal a complex organization of regulatory elements required for generating single cell Pcdh diversity.