Paper List
-
Pharmacophore-based design by learning on voxel grids
This paper addresses the computational bottleneck and limited novelty in conventional pharmacophore-based virtual screening by introducing a voxel cap...
-
CONFIDE: Hallucination Assessment for Reliable Biomolecular Structure Prediction and Design
This paper addresses the critical limitation of current protein structure prediction models (like AlphaFold3) where high-confidence scores (pLDDT) can...
-
On the Approximation of Phylogenetic Distance Functions by Artificial Neural Networks
This paper addresses the core challenge of developing computationally efficient and scalable neural network architectures that can learn accurate phyl...
-
EcoCast: A Spatio-Temporal Model for Continual Biodiversity and Climate Risk Forecasting
This paper addresses the critical bottleneck in conservation: the lack of timely, high-resolution, near-term forecasts of species distribution shifts ...
-
Training Dynamics of Learning 3D-Rotational Equivariance
This work addresses the core dilemma of whether to use computationally expensive equivariant architectures or faster symmetry-agnostic models with dat...
-
Fast and Accurate Node-Age Estimation Under Fossil Calibration Uncertainty Using the Adjusted Pairwise Likelihood
This paper addresses the dual challenge of computational inefficiency and sensitivity to fossil calibration errors in Bayesian divergence time estimat...
-
Few-shot Protein Fitness Prediction via In-context Learning and Test-time Training
This paper addresses the core challenge of accurately predicting protein fitness with only a handful of experimental observations, where data collecti...
-
scCluBench: Comprehensive Benchmarking of Clustering Algorithms for Single-Cell RNA Sequencing
This paper addresses the critical gap of fragmented and non-standardized benchmarking in single-cell RNA-seq clustering, which hinders objective compa...
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.