CCCTC-binding factor (CTCF) is a multifunctional zinc finger protein that is conserved in metazoan species. CTCF is consistently found to play an important role in many diverse biological processes. CTCF/cohesin-mediated active chromatin ‘loop extrusion’ architects three-dimensional (3D) genome folding. The 3D architectural role of CTCF underlies its multifarious functions, including developmental regulation of gene expression, protocadherin (Pcdh) promoter choice in the nervous system, immunoglobulin (Ig) and T-cell receptor (Tcr) V(D)J recombination in the immune system, homeobox (Hox) gene control during limb development, as well as many other aspects of biology. Here, we review the pleiotropic functions of CTCF from the perspective of its essential role in 3D genome architecture and topological promoter/enhancer selection. We envision the 3D genome as an enormous complex architecture, with tens of thousands of CTCF sites as connecting nodes and CTCF proteins as mysterious bonds that glue together genomic building parts with distinct articulation joints. In particular, we focus on the internal mechanisms by which CTCF controls higher order chromatin structures that manifest its many façades of physiological and pathological functions. We also discuss the dichotomic role of CTCF sites as intriguing 3D genome nodes for seemingly contradictory ‘looping bridges’ and ‘topological insulators’ to frame a beautiful magnificent house for a cell's nuclear home.

CCCTC结合因子（CTCF）是在后生动物物种中保守的多功能锌指蛋白。始终发现CTCF在许多不同的生物学过程中都起着重要作用。CTCF / cohesin介导的活性染色质“环挤出”可构建三维（3D）基因组折叠。CTCF的3D结构作用是其多种功能的基础，包括基因表达的发育调控，神经系统中原钙粘蛋白（Pcdh）启动子的选择，免疫球蛋白（Ig）和T细胞受体（Tcr）V（D）J重组系统，homeobox（Hox）肢体发育过程中的基因控制，以及生物学的许多其他方面。在这里，我们从CTCF在3D基因组结构和拓扑启动子/增强子选择中的重要作用的角度来回顾其功能。我们将3D基因组设想为一个巨大的复杂体系结构，其中成千上万个CTCF位点作为连接节点，而CTCF蛋白则作为神秘的键，将具有独特关节的基因组构建部分粘合在一起。特别是，我们专注于CTCF控制高阶染色质结构的内部机制，这些结构表现出其许多生理和病理功能的外观。