Promoter cross-talk via a shared enhancer explains paternally biased expression of Nctc1 at the Igf2/H19/Nctc1 imprinted locus.
Promoter cross-talk via a shared enhancer explains paternally biased expression of Nctc1 at the Igf2/H19/Nctc1 imprinted locus.
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DOI：
10.1093/nar/gks1182
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发表时间：
2013-01
影响因子：
14.9
通讯作者：
Pfeifer K
中科院分区：
文献类型：
--
作者：
Eun B;Sampley ML;Good AL;Gebert CM;Pfeifer K
发育调控的转录通常依赖于远端增强子与其同源启动子之间的物理相互作用。最近的基因组分析表明，启动子-启动子相互作用可能在组织基因组和建立细胞类型特异性基因表达中发挥类似的关键作用。Igf 2/H19位点是阐明顺式调控元件之间长程相互作用的一个有价值的模型。连锁的、双印记基因的印记表达通过父本Igf 2或母本H19启动子与其共享的组织特异性增强子元件之间的亲本来源特异性染色体环结构来解释。在这里，我们进一步分析了这些环结构的组成及其对连接的长非编码RNA Nctc 1表达的影响。我们发现，Nctc 1与Igf 2和H19共同调节，并与共享的肌肉增强子相互作用。事实上，所有三个共调节基因都有可能不仅与共享的增强子相互作用，而且通过它们的增强子相互作用彼此相互作用。此外，发育和遗传分析表明这些启动子-启动子相互作用的功能意义。总之，我们提出了一种新的机制来解释Nctc 1的发育特异性印迹，并提供了新的信息增强机制和染色质结构域在建立基因表达模式的作用。
Developmentally regulated transcription often depends on physical interactions between distal enhancers and their cognate promoters. Recent genomic analyses suggest that promoter–promoter interactions might play a similarly critical role in organizing the genome and establishing cell-type-specific gene expression. The Igf2/H19 locus has been a valuable model for clarifying the role of long-range interactions between cis-regulatory elements. Imprinted expression of the linked, reciprocally imprinted genes is explained by parent-of-origin-specific chromosomal loop structures between the paternal Igf2 or maternal H19 promoters and their shared tissue-specific enhancer elements. Here, we further analyze these loop structures for their composition and their impact on expression of the linked long non-coding RNA, Nctc1. We show that Nctc1 is co-regulated with Igf2 and H19 and physically interacts with the shared muscle enhancer. In fact, all three co-regulated genes have the potential to interact not only with the shared enhancer but also with each other via their enhancer interactions. Furthermore, developmental and genetic analyses indicate functional significance for these promoter–promoter interactions. Altogether, we present a novel mechanism to explain developmental specific imprinting of Nctc1 and provide new information about enhancer mechanisms and about the role of chromatin domains in establishing gene expression patterns.
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