Modulation of DNA rheology by a transcription factor that forms aging microgels

TL;DR

This study reveals that the transcription factor NANOG forms aging microgel-like structures at high concentrations, influencing DNA rheology and potentially regulating gene expression through mechanical stabilization.

Contribution

It uncovers the formation of aging microgels by NANOG and their role in modulating DNA rheology, combining experimental and computational approaches.

Findings

NANOG forms macroscopic aging gels at high concentrations.

NANOG creates self-limiting micelle-like clusters exposing DNA-binding domains.

NANOG structures stabilize genome dynamics and may enable mechanical memory.

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 in sustaining embryonic stem cell self-renewal. We discover that at high concentrations NANOG forms macroscopic aging gels through its intrinsically disordered tryptophan-rich domain. By combining molecular dynamics simulations, mass photometry and Cryo-EM, we also discover that NANOG forms self-limiting micelle-like clusters which expose their DNA-binding domains. In dense solutions of DNA, NANOG micelle-like structures stabilize intermolecular entanglements and crosslinks, forming microgel-like structures. Our findings suggest that NANOG may contribute to regulate gene expression in a unconventional way: by restricting and stabilizing genome dynamics at key transcriptional sites through the formation of an aging microgel-like structure, potentially enabling mechanical memory in the gene network.