NANOG assembles into self-limiting aging micelles that drive a sol-gel transition and modulate DNA dynamics

Abstract

Proteins and nucleic acids form non-Newtonian liquids with complex rheological properties that contribute to their function in vivo. Here we investigate the rheology of the transcription factor NANOG, a key protein to maintain embryonic stem cell pluripotency. We find that at high concentrations, NANOG forms macroscopic aging gels that are dependent on its intrinsically disordered domain. By combining molecular dynamics simulations, mass photometry and Cryo-EM, we also discover that - in contrast with unbounded condensates formed by other intrinsically disordered proteins - NANOG forms self-limiting micelles with exposed DNA-binding domains. We show that these micelles can stabilize DNA entanglements and in turn modulate DNA dynamics. Based on our findings, we conjecture that NANOG may contribute to regulate gene expression by creating local gel-like environments that restrict genome dynamics and that its aging may ingrain mechanical memory in gene regulatory networks.