Molecular mechanism of directional CTCF recognition of a diverse range of genomic sites
Molecular mechanism of directional CTCF recognition of a diverse range of genomic sites
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CTCF定向识别多种基因组位点的分子机制
DOI：
10.1038/cr.2017.131
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发表时间：
2017-11-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Yanli
中科院分区：
文献类型：
--
作者：
Yin, Maolu;Wang, Jiuyu;Wang, Yanli
CTCF是一种保守的3D基因组结构蛋白，它的11个锌指（ZFs）通过与CTCF结合位点（CBSs）内4个模块的特定序列元件定向结合，决定了正确的全基因组染色质成环相互作用。在这里，我们报告四个晶体结构的人CTCF在复杂的CBS的原钙粘蛋白（Pcdh）集群。我们表明，通过将其ZF 3、ZF 4-7和ZF 9-11沿着沿着CBS插入到大沟中，实现了CTCF与Pcdh增强子和启动子的同源CBS的定向结合，从而分别导致模块4、模块3和2以及模块1的序列特异性识别;并且ZF 8充当模块1和2之间可变距离的间隔元件。此外，与模块2-3的中心位置的不对称“A”的碱基接触对于具有对称核心序列但缺少模块1的CBS的定向识别是必要的。此外，CTCF耐受简并CBS序列内特定位置处的碱基变化，允许全基因组CTCF与多种CBS结合。总之，这些复杂的结构为多价CTCF与整个人类基因组中的同源位点结合的方向性、多样性、灵活性、动态性和保守性的分子机制提供了重要的见解。
CTCF, a conserved 3D genome architecture protein, determines proper genome-wide chromatin looping interactions through directional binding to specific sequence elements of four modules within numerous CTCF-binding sites (CBSs) by its 11 zinc fingers (ZFs). Here, we report four crystal structures of human CTCF in complex with CBSs of the protocadherin (Pcdh) clusters. We show that directional CTCF binding to cognate CBSs of the Pcdh enhancers and promoters is achieved through inserting its ZF3, ZFs 4-7, and ZFs 9-11 into the major groove along CBSs, resulting in a sequence-specific recognition of module 4, modules 3 and 2, and module 1, respectively; and ZF8 serves as a spacer element for variable distances between modules 1 and 2. In addition, the base contact with the asymmetric “A” in the central position of modules 2-3, is essential for directional recognition of the CBSs with symmetric core sequences but lacking module 1. Furthermore, CTCF tolerates base changes at specific positions within the degenerated CBS sequences, permitting genome-wide CTCF binding to a diverse range of CBSs. Together, these complex structures provide important insights into the molecular mechanisms for the directionality, diversity, flexibility, dynamics, and conservation of multivalent CTCF binding to its cognate sites across the entire human genome.