Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice
Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice
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DOI：
10.1016/j.cell.2019.03.008
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发表时间：
2019-04-18
期刊：
影响因子：
64.5
通讯作者：
Maniatis, Tom
中科院分区：
文献类型：
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作者：
Canzio, Daniele;Nwakeze, Chiamaka L.;Maniatis, Tom
成簇的原钙粘蛋白（Pcdh）α、β和γ基因的随机激活在神经回路组装中起作用的单个神经元中产生细胞表面身份代码。在这里，我们表明，Pcdh α基因的选择涉及激活位于每个Pcdh α交替基因的第一个外显子的反义启动子。从该反义启动子转录的反义长非编码RNA（lncRNA）延伸通过有义启动子，导致每个启动子附近的CTCF结合位点的DNA去甲基化。去甲基化依赖性CTCF与两个启动子的结合促进了具有远端增强子（HS 5 -1）的粘附素介导的DNA成环，从而锁定所选Pcdh α基因的转录状态。解偶联DNA去甲基化从反义转录Tet 3过表达在小鼠嗅觉神经元促进CTCF结合所有Pcdh α启动子，导致邻近偏向的DNA循环的HS 5 -1增强子。因此，反义转录介导的启动子去甲基化作为一种非距离依赖性增强子/启动子DNA环的机制，以确保随机Pcdh α启动子的选择。
Stochastic activation of clustered Protocadherin (Pcdh) alpha, beta, and gamma genes generates a cell-surface identity code in individual neurons that functions in neural circuit assembly. Here, we show that Pcdh alpha gene choice involves the activation of an antisense promoter located in the first exon of each Pcdh alpha alternate gene. Transcription of an antisense long noncoding RNA (lncRNA) from this antisense promoter extends through the sense promoter, leading to DNA demethylation of the CTCF binding sites proximal to each promoter. Demethylation-dependent CTCF binding to both promoters facilitates cohesin-mediated DNA looping with a distal enhancer (HS5-1), locking in the transcriptional state of the chosen Pcdh alpha gene. Uncoupling DNA demethylation from antisense transcription by Tet3 overexpression in mouse olfactory neurons promotes CTCF binding to all Pcdh alpha promoters, resulting in proximity-biased DNA looping of the HS5-1 enhancer. Thus, antisense transcription-mediated promoter demethylation functions as a mechanism for distance-independent enhancer/promoter DNA looping to ensure stochastic Pcdh alpha promoter choice.