The Topology of Cellular Ontogeny

Citation

Flores-Bautista, Emanuel (2025) The Topology of Cellular Ontogeny. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/t8hc-yq15. https://resolver.caltech.edu/CaltechTHESIS:06022025-234901151

Abstract

A fundamental goal of modern biology is to build global, predictive models of gene regulation that encompass diverse physiological contexts. Single-cell transcriptomics has enabled the creation of developmental cell atlases--detailed catalogs of gene expression patterns and differentiation trajectories at an organismal scale. The widespread availability of cell atlases across metazoan model organisms presents an opportunity to construct global theories of cell-state control. In this thesis, we introduce a framework that uses persistent homology to decompose cell atlases into topological structures that provide signatures of gene regulation at the scale of an organism. Using this framework, we found that the topological structure of a broad set of developmental atlases contains only a discrete set of topological structures—such as clusters, trees, and loops—-revealing the recurrent use of global gene regulatory strategies. Our analysis revealed that the tree topology, while predominant, is not universal. Indeed, we identified non-trivial topologies containing loops in the development of human immune cells, seam-hypodermal cells in \textit{C. elegans}, and the cnidocytes of multiple cnidarians. Analysis of cell-state manifolds with non-trivial topology demonstrated an important role of convergent structures in increasing cellular diversity along paths to a common cell fate, and of cyclic structures in self-renewal of progenitor-like states. Together, this work provides a global perspective on principles of cell-state regulation, and suggests that loops are important organizing structures for controlling cell differentiation.

Thesis Files