The genomic landscape of cohesin-associated chromatin interactions

Cohesin is implicated in establishing tissue-specific DNA loops that target enhancers to promoters, and also localizes to sites bound by the insulator protein CTCF, which blocks enhancer-promoter communication. However, cohesin-associated interactions have not been characterized on a genome-wide scale. Here we performed chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) of the cohesin subunit SMC1A in developing mouse limb. We identified 2,264 SMC1A interactions, of which 1,491 (65%) involved sites co-occupied by CTCF. SMC1A participates in tissue- specific enhancer-promoter interactions and interactions that demarcate regions of correlated regulatory output. In contrast to previous studies, we also identified interactions between promoters and distal sites that are maintained in multiple tissues, but are poised in embryonic stem cells and resolve to tissue-specific activated or repressed chromatin states in the mouse embryo. Our results reveal the diversity of cohesin- associated interactions in the genome and highlight their role in establishing the regulatory architecture of development. Smc1a ChIA-PET, RNA-seq, chromatin state maps (H3K27ac, H3K27me3, H3K4m2), and CTCF and Smc1a binding in mouse embryonic limb bud (E11.5)黏连蛋白（cohesin）参与构建将增强子靶向引导至启动子的组织特异性DNA环，同时定位于绝缘子蛋白CTCF的结合位点——CTCF可阻断增强子与启动子之间的通讯。 然而，目前尚未在全基因组尺度上系统表征黏连蛋白相关的染色质互作。 本研究针对发育中小鼠肢体组织内的黏连蛋白亚基SMC1A，开展了配对末端标签测序染色质互作分析（ChIA-PET, chromatin interaction analysis with paired-end tag sequencing）。我们共鉴定出2264个SMC1A相关互作位点，其中1491个（占比65%）涉及CTCF共同结合的基因组区域。 SMC1A参与介导组织特异性增强子-启动子互作，以及划分具有关联调控输出的基因组区域的互作。与既往研究结论不同的是，我们还鉴定出了在多种组织中保守存在的启动子与远端位点之间的互作：这类互作在胚胎干细胞中处于 poised 状态，并在小鼠胚胎发育过程中分化为组织特异性激活或抑制的染色质状态。 本研究结果揭示了基因组内黏连蛋白相关互作的多样性，并凸显了其在构建发育调控基因组架构中的核心作用。 本研究附带的组学数据集包括：Smc1a ChIA-PET数据、RNA测序（RNA-seq）数据、染色质状态图谱（涵盖H3K27ac、H3K27me3、H3K4m2），以及小鼠胚胎肢芽（E11.5时期）中的CTCF与Smc1a结合数据。