Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency

Cell Syst. 2018 Nov 28;7(5):482-495.e10. doi: 10.1016/j.cels.2018.09.003. Epub 2018 Nov 7.

Abstract

The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.

Keywords: CTCF; CTCF loops; chromatin architecture; chromatin loops; chromatin structure; differentiation; pluripotency; topologically associating domains.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Chromatin / metabolism*
  • Chromatin / ultrastructure
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cohesins
  • Mice
  • Mouse Embryonic Stem Cells / metabolism*
  • Mouse Embryonic Stem Cells / physiology
  • Mouse Embryonic Stem Cells / ultrastructure
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / physiology
  • Neural Stem Cells / ultrastructure
  • Protein Binding

Substances

  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Ctcf protein, mouse