Paper List
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Exactly Solvable Population Model with Square-Root Growth Noise and Cell-Size Regulation
This paper addresses the fundamental gap in understanding how microscopic growth fluctuations, specifically those with size-dependent (square-root) no...
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Assessment of Simulation-based Inference Methods for Stochastic Compartmental Models
This paper addresses the core challenge of performing accurate Bayesian parameter inference for stochastic epidemic models when the likelihood functio...
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Realistic Transition Paths for Large Biomolecular Systems: A Langevin Bridge Approach
This paper addresses the core challenge of generating physically realistic and computationally efficient transition paths between distinct protein con...
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MoRSAIK: Sequence Motif Reactor Simulation, Analysis and Inference Kit in Python
This work addresses the computational bottleneck in simulating prebiotic RNA reactor dynamics by developing a Python package that tracks sequence moti...
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The BEAT-CF Causal Model: A model for guiding the design of trials and observational analyses of cystic fibrosis exacerbations
This paper addresses the critical gap in cystic fibrosis exacerbation management by providing a formal causal framework that integrates expert knowled...
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A Theoretical Framework for the Formation of Large Animal Groups: Topological Coordination, Subgroup Merging, and Velocity Inheritance
This paper addresses the core problem of how large, coordinated animal groups form in nature, challenging the classical view of gradual aggregation by...
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ANNE Apnea Paper
This paper addresses the core challenge of achieving accurate, event-level sleep apnea detection and characterization using a non-intrusive, multimoda...
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DeeDeeExperiment: Building an infrastructure for integrating and managing omics data analysis results in R/Bioconductor
This paper addresses the critical bottleneck of managing and organizing the growing volume of differential expression and functional enrichment analys...
Modulation of DNA rheology by a transcription factor that forms aging microgels
University of Edinburgh | University of Glasgow | MRC Human Genetics Unit | WPI-SKCM2, Hiroshima University
The 30-Second View
IN SHORT: This work addresses the fundamental question of how the transcription factor NANOG, essential for embryonic stem cell pluripotency, physically regulates gene expression beyond simple DNA binding, by revealing its ability to form self-limiting, aging microgels that modulate DNA rheology.
Innovation (TL;DR)
- Methodology First demonstration that a transcription factor (NANOG) forms self-limiting micelle-like clusters (~22-25 monomers) with exposed DNA-binding domains, acting as transient cross-linkers for DNA molecules.
- Biology Discovery of an aging microgel formation by NANOG, where viscoelasticity increases over time (10,000-fold viscosity increase over 12h), driven by its intrinsically disordered tryptophan-rich (WR) domain.
- Theory Proposes a novel 'rheological gene regulation' paradigm: NANOG may regulate gene expression not by large-scale chromatin reorganization, but by stabilizing and restricting the *dynamics* of key regulatory sites via aging condensates, potentially ingraining mechanical memory.
Key conclusions
- Wild-type NANOG forms macroscopic aging gels (10,000-fold viscosity increase over 12h at 37°C) and self-limiting micelle-like clusters (~22-25 proteins), while the oligomerization-deficient mutant (W10A) does not.
- Both clustering (via WR domain) and DNA binding (via homeodomain) are required for NANOG to act as an effective DNA cross-linker, significantly enhancing the viscoelasticity of entangled DNA solutions (observed in WT but not in W10A or DNA-binding-deficient N51A mutants).
- Aging (increasing viscoelasticity over time) occurs in NANOG-DNA solutions for both WT and the DNA-binding-deficient N51A mutant, indicating that oligomerization alone is sufficient to drive this slow restructuring toward gel-like states.
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 inter-molecular 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.