Identification of long-range regulatory elements in the protocadherin-α gene cluster
Identification of long-range regulatory elements in the protocadherin-α gene cluster
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DOI：
10.1073/pnas.0609445104
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发表时间：
2006-12-26
影响因子：
11.1
通讯作者：
Maniatis, Tom
中科院分区：
文献类型：
--
作者：
Ribich, Scott;Tasic, Bosiljka;Maniatis, Tom
成簇的原钙粘蛋白（Pcdh）由三个紧密相连的基因簇（Pcdh-α，-β和-γ）编码，这些基因簇跨越近100万个DNA碱基对。Pcdh-a基因簇编码14种不同的钙粘蛋白样细胞表面蛋白，其在神经元中表达并存在于突触连接处。单个Pcdh-a mRNA是由14个“可变”（V）外显子和3个“恒定”外显子中的一个组装而成，该过程涉及差异启动子激活和可变前mRNA剪接。在单个神经元中，每条染色体上只有一个（很少有两个）Pcdh α 1-12启动子被独立和随机激活。因此，在大多数细胞中，这种不寻常的单等位基因表达形式导致两个不同的Pcdh-α 1-12 V外显子的表达，每个染色体一个。簇中剩余的两个V外显子（Pcdh-α C1和α C2）在每个神经元中双等位基因表达。Pcdh-a基因簇中启动子选择和单等位基因表达的机制尚不清楚。在这里，我们报告的两个远程顺式调控元件的Pcdh-a基因簇，HS 5 -1和HS 7的识别。我们表明，HS 5 -1是需要从Pcdh α 1-12和α C1启动子的最大水平的表达，但不是Pcdh-α C2启动子。HS 5 -1元件的近簇范围的要求与Pcdh-α V外显子的单等位基因表达是单个V外显子启动子对两个调控元件之间竞争的结果的可能性一致。
The clustered protocadherins (Pcdh) are encoded by three closely linked gene clusters (Pcdh-alpha, -beta, and -gamma) that span nearly 1 million base pairs of DNA. The Pcdh-a gene cluster encodes a family of 14 distinct cadherin-like cell surface proteins that are expressed in neurons and are present at synaptic junctions. Individual Pcdh-a mRNAs are assembled from one of 14 "variable" (V) exons and three "constant" exons in a process that involves both differential promoter activation and alternative pre-mRNA splicing. in individual neurons, only one(and rarelytwo) of thePcdh alpha 1-12 promoters is independently and randomly activated on each chromosome. Thus, in most cells, this unusual form of monoallelic expression leads to the expression of two different Pcdh-alpha 1-12 V exons, one from each chromosome. The two remaining V exons in the cluster (Pcdh-alpha C1 and alpha C2) are expressed biallelically in every neuron. The mechanisms that underlie promoter choice and monoallelic expression in the Pcdh-a gene cluster are not understood. Here we report the identification of two long-range cis-regulatory elements in the Pcdh-a gene cluster, HS5-1 and HS7. We show that HS5-1 is required for maximal levels of expression from the Pcdh alpha 1-12 and alpha C1 promoters, but not the Pcdh-alpha C2 promoter. The nearly cluster-wide requirement of the HS5-1 element is consistent with the possibility that the monoallelic expression of Pcdh-alpha V exons is a consequence of competition between individual V exon promoters for the two regulatory elements.