NANOG prion-like assembly mediates DNA bridging to facilitate chromatin reorganization and activation of pluripotency

Nat Cell Biol. 2022 May;24(5):737-747. doi: 10.1038/s41556-022-00896-x. Epub 2022 Apr 28.

Abstract

Human NANOG expression resets stem cells to ground-state pluripotency. Here we identify the unique features of human NANOG that relate to its dose-sensitive function as a master transcription factor. NANOG is largely disordered, with a C-terminal prion-like domain that phase-transitions to gel-like condensates. Full-length NANOG readily forms higher-order oligomers at low nanomolar concentrations, orders of magnitude lower than typical amyloids. Using single-molecule Förster resonance energy transfer and fluorescence cross-correlation techniques, we show that NANOG oligomerization is essential for bridging DNA elements in vitro. Using chromatin immunoprecipitation sequencing and Hi-C 3.0 in cells, we validate that NANOG prion-like domain assembly is essential for specific DNA recognition and distant chromatin interactions. Our results provide a physical basis for the indispensable role of NANOG in shaping the pluripotent genome. NANOG's unique ability to form prion-like assemblies could provide a cooperative and concerted DNA bridging mechanism that is essential for chromatin reorganization and dose-sensitive activation of ground-state pluripotency.

MeSH terms

  • Chromatin* / genetics
  • DNA / genetics
  • Humans
  • Nanog Homeobox Protein / genetics
  • Prions* / genetics

Substances

  • Chromatin
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Prions
  • DNA