CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene–enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.

CpG 岛 (CGI) 代表了脊椎动物基因组的一个普遍特征，与约 70% 的基因启动子相关。 CGI 通过赋予附近启动子独特的染色质特性来控制转录起始。此外，还有数千个远端或孤立 CGI (oCGI)，其功能相关性几乎不为人所知。在这里，我们证明 oCGI 是平衡增强子的重要组成部分，可以增强其远程调节活性并控制其靶基因的反应性。在小鼠胚胎干细胞中使用敲入策略，我们在包含具有不同类型启动子的基因的拓扑关联域内引入了具有或不具有oCGI的平衡增强子。对所得细胞系的分析表明，oCGI 作为束缚元件，促进平衡增强子和远端基因之间的物理和功能通讯，特别是那些在其启动子中具有大 CGI 簇的基因。因此，通过充当基因增强子相容性的遗传决定因素，CGI 可以有助于生理和潜在病理条件下的基因表达控制。