Nanog Prion-like Assembly Mediates Dna Bridging to Facilitate Chromatin Reorganization and Activation of Pluripotency

Authors

Kyoung-Jae Choi
My Diem Quan
Chuangye Qi
Joo-Hyung Lee
Phoebe S Tsoi
Mahla Zahabiyon
Aleksandar Bajic
Liya Hu
B V Venkataram Prasad
Shih-Chu Jeff Liao
Wenbo Li
Allan Chris M Ferreon
Josephine C Ferreon

Publication Date

5-1-2022

Journal

National Cell Biology

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.

Keywords

Chromatin, DNA, Humans, Nanog Homeobox Protein, Prions