Noise-Driven Differentiation via Gene Frustration and Epigenetic Fixation

2026/04/20 by Davey Plugers, Kunihiko Kaneko · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Physics and Astronomy · #physics.bio-ph #q-bio.MN

paper · pdf

12 pages, 5 figures

arxiv published 2026/04/20 · arxiv created 2026/08/05 · arxiv updated 2026/08/06

Abstract

Gene expression in cells is stochastic, yet differentiation can display reproducible timing and stable fate commitment. We develop an analytical theory for a previously identified mechanism in which weakly stable intermediate, or frustrated, gene-expression states are perturbed by stochastic fluctuations and subsequently fixed by slow epigenetic feedback. By eliminating the fast expression dynamics, we show that the differentiation of the slow epigenetic variable is driven by the noise of gene-expression, which can be amplified by regulatory interactions. We derive the logarithmic dependence of onset time for differentiation upon the effective noise intensity, and the input-dependent probability of reaching either fate. We further construct a Waddington-inspired time-dependent probability landscape that visualizes population branching and progressive fate fixation.

Citations

• Feedback-mediated circulation and persistence of stochastic fluctuations in gene regulatory circuits
• Optimality as a framework for understanding developmental robustness
• Mapping, modeling, and reprogramming cell-fate decision making systems
• Analog epigenetic memory revealed by targeted chromatin editing
• A Waddington landscape for prototype learning in generalized Hopfield networks
• Decoding the mechanisms underlying cell-fate decision-making during stem cell differentiation by Random Circuit Perturbation
• Noise control and utility: from regulatory network to spatial patterning
• Homeorhesis in Waddington's Landscape by Epigenetic Feedback Regulation
• Control of stochastic and induced switching in biophysical networks
• Bifurcation dynamics in lineage-commitment in bipotent progenitor cells
• Evolution of Robustness to Noise and Mutation in Gene Expression Dynamics
• The role of input noise in transcriptional regulation
• Ubiquity of Log-normal Distributions in Intra-cellular Reaction Dynamic
• Theory of Robustness of Irreversible Differentiation in a Stem Cell System: Chaos hypothesis
• Transitions Induced by the Discreteness of Molecules in a Small Autocatalytic System
• The Strategy of the Genes

Discussions

• Our second paper is now out on arXiv. In this work we look at how intermediately expressed ("frustrated") genes can be combined with noise leading to differentiation: arxiv.org/abs/2604.18185 [bsky, 0 points, 0 comments]

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