CTCF organizes inter-A compartment interactions through RYBP-dependent phase separation

Cell Res. 2022 Aug;32(8):744-760. doi: 10.1038/s41422-022-00676-0. Epub 2022 Jun 29.


Chromatin is spatially organized into three-dimensional structures at different levels including A/B compartments, topologically associating domains and loops. The canonical CTCF-mediated loop extrusion model can explain the formation of loops. However, the organization mechanisms underlying long-range chromatin interactions such as interactions between A-A compartments are still poorly understood. Here we show that different from the canonical loop extrusion model, RYBP-mediated phase separation of CTCF organizes inter-A compartment interactions. Based on this model, we designed and verified an induced CTCF phase separation system in embryonic stem cells (ESCs), which facilitated inter-A compartment interactions, improved self-renewal of ESCs and inhibited their differentiation toward neural progenitor cells. These findings support a novel and non-canonical role of CTCF in organizing long-range chromatin interactions via phase separation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCCTC-Binding Factor / metabolism
  • Cell Differentiation
  • Chromatin Assembly and Disassembly
  • Chromatin*
  • Embryonic Stem Cells / metabolism
  • Neural Stem Cells* / metabolism


  • CCCTC-Binding Factor
  • Chromatin