Genetic evidence for asymmetric blocking of higher-order chromatin structure by CTCF/cohesin
Genetic evidence for asymmetric blocking of higher-order chromatin structure by CTCF/cohesin
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DOI：
10.1007/s13238-019-00656-y
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发表时间：
2019-09
期刊：
影响因子：
21.1
通讯作者：
Yujia Lu;Jia Shou;Zhilian Jia;Yonghu Wu;Jin-huan Li;Ya Guo;Qiang Wu
中科院分区：
文献类型：
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作者：
Yujia Lu;Jia Shou;Zhilian Jia;Yonghu Wu;Jin-huan Li;Ya Guo;Qiang Wu
与多肽链高阶折叠成功能蛋白类似，线性DNA分子在真核细胞核中以分层和动态方式空间折叠成三维（3D）功能染色质结构（Huang和Wu，2016;罗利和Corces，2018）。这种动态折叠与许多核过程密切相关，例如DNA复制和修复，染色体易位，重组和分离，以及RNA转录，剪接和运输。特别是，动态长距离染色质成环相互作用（导致远端增强子和靶启动子之间的紧密空间接触）被认为在动物发育期间控制精确的时空以及细胞类型特异性基因表达方面发挥作用（罗利和Corces，2018）。哺乳动物基因组中含有许多非编码调控元件，这些非编码调控元件调节这些动态的长距离染色质成环相互作用。特别是，一种称为绝缘体的遗传元件在确保远端增强子正确激活靶启动子方面发挥着微妙的作用（Huang和Wu，2016）。在哺乳动物中，最突出的绝缘体结合蛋白是CCCTC结合因子（CTCF），其是具有3D基因组组织所必需的11个锌指的结构蛋白（Yin等人，2017; Wu等人，2019). CTCF动态地和定向地结合数十万个基因组位点，并且这种结合对于其在许多细胞和发育过程中的多价作用是关键的（Guo et al.，2015年; Yin等人，2017年）。特别地，CTCF与其相关的粘附素复合物协作，决定免疫系统中Bcr（B细胞受体）和Tcr（T细胞受体）基因簇的V（D）J重组（Jain等人，2018年; Wu等人，2019）和神经系统中原钙粘蛋白（Pcdh）基因簇的启动子选择（Guo et al.，2012; Mountoufaris等人，2018; Canzio等人，2019年; Wu等人，2019年）。成簇的Pcdh基因已被用作研究高阶染色质折叠机制的模型基因（图1A）。例如，在小鼠中，58个成簇的Pcdh基因线性地组织成α、β和γ的三个紧密连锁的簇（图S1 A）（Wu
Similar to higher-order folding of polypeptide chains into functional proteins, linear DNA molecules are spatially folded in a hierarchical and dynamic manner into three-dimensional (3D) functional chromatin structures in eukaryotic nuclei (Huang and Wu, 2016; Rowley and Corces, 2018). This dynamic folding is closely related to many nuclear processes such as DNA replication and repair, chromosomal translocation, recombination, and segregation, as well as RNA transcription, splicing, and transport. In particular, dynamic long-distance chromatin looping interactions, which result in close spatial contacts between distal enhancers and target promoters, are thought to play a role in controlling precise spatiotemporal as well as cell-type specific gene expression during animal development (Rowley and Corces, 2018). Mammalian genomes contain numerous noncoding regulatory elements that regulate these dynamic long-distance chromatin looping interactions. Specially, one type of genetic elements, known as insulators, plays a delicate role to ensure proper activation of target promoters by distal enhancers (Huang and Wu, 2016). In mammals, the most prominent insulator-binding protein is CCCTC binding factor (CTCF), an architectural protein with 11 zinc-fingers essential for 3D genome organization (Yin et al., 2017; Wu et al., 2019).CTCF dynamically and directionally binds to hundreds of thousands genomic sites and this binding is pivotal for its multivalent role in many cellular and developmental processes (Guo et al., 2015; Yin et al., 2017). In particular, CTCF, in collaboration with its associated cohesin complex, determines V (D) J recombination of the Bcr (B-cell receptor) and Tcr (T-cell receptor) gene clusters in the immune system (Jain et al., 2018; Wu et al., 2019) and promoter choice of the protocadherin (Pcdh) gene clusters in the nervous system (Guo et al., 2012; Mountoufaris et al., 2018; Canzio et al., 2019; Wu et al., 2019). The clustered Pcdh genes have been used as model genes for investigating mechanisms of higher-order chromatin folding (Fig. 1 A). In mice, for example, 58 clustered Pcdh genes are linearly organized into three closely-linked clusters of the α, β, and γ (Fig. S1A)(Wu