The Energetics and Physiological Impact of Cohesin Extrusion

Cell. 2018 May 17;173(5):1165-1178.e20. doi: 10.1016/j.cell.2018.03.072. Epub 2018 Apr 26.

Abstract

Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.

Keywords: CTCF; DNA damage; Nipbl; chromosomal translocations; class switching; cohesin; loop extrusion; nuclear architecture; topoisomerase II.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism
  • CCCTC-Binding Factor / genetics
  • CCCTC-Binding Factor / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Chondroitin Sulfate Proteoglycans / genetics
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosomes / metabolism
  • Genome*
  • Humans
  • Mice
  • Mutagenesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Cspg6 protein, mouse
  • Nipbl protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • Rad21 protein, mouse
  • Transcription Factors
  • cohesins
  • Adenosine Triphosphate