Generative epigenetic landscapes map the topology and topography of cell fates

• 成果类型: Article
• 署名作者: Mochulska, Victoria; Francois, Paul
• 署名单位: McGill University; Universite de Montreal; Mila Quebec Artificial Intelligence Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2514508122
• 发表日期: 2025-12-16
• 页码: e2514508122
• 关键词: Waddington landscape; cellular differentiation; EVOLUTION; dynamical systems; mathematical modeling; SEGMENTATION CLOCK; vertebrate segmentation; gene; geometry; DYNAMICS

摘要

Epigenetic landscapes were proposed by Waddington as the central concept to describe cell fate dynamics in a locally low-dimensional space. In modern landscape models, attractors represent cell types, and stochastic jumps and bifurcations drive cellular decisions, allowing for quantitative and predictive descriptions. However, given a biological problem of interest, we still lack tools to infer and build possible Waddington landscapes systematically. In this study, we propose a generative model for deriving epigenetic landscapes compatible with data. To build the landscapes, we combine gradient and rotational vector fields composed of locally weighted elements that encode valleys of the Waddington landscape, resulting in interpretable models. We optimize landscapes through computational evolution and illustrate our approach with two developmental examples: metazoan segmentation and neuromesoderm differentiation. In both cases, we obtain ensembles of solutions that reveal both known and original landscapes in terms of topology and bifurcations. Conversely, topographic features appear strongly constrained by dynamical data, which suggests that our approach can generically derive interpretable and predictive epigenetic landscapes.