Many facades of CTCF unified by its coding for three-dimensional genome architecture

J Genet Genomics. 2020 Aug;47(8):407-424. doi: 10.1016/j.jgg.2020.06.008. Epub 2020 Sep 1.


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.

Keywords: 3D genome; CTCF; Distal enhancer; Loop extrusion; Target promoter; Topological insulator.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites / genetics
  • CCCTC-Binding Factor / genetics*
  • Cell Cycle Proteins / genetics
  • Chromatin / genetics*
  • Chromosomal Proteins, Non-Histone / genetics
  • Enhancer Elements, Genetic / genetics
  • Genome, Human / genetics*
  • Humans
  • Promoter Regions, Genetic / genetics
  • Receptors, Antigen, T-Cell / genetics


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Receptors, Antigen, T-Cell
  • cohesins