{ "abstract": "Eukaryotic cells are spatially organized into functionally-distinct compartments. This three-dimensional (3D) organization generates intracellular heterogeneities that can modulate regulatory dynamics. Despite this knowledge of subcellular organization, most quantitative gene-regulation models still assume a well-mixed environment in which molecules can react regardless of their spatial positions. Here, we use the well-established galactose switch in budding yeast (Saccharomyces cerevisiae) to develop spatially-resolved models that integrate experimentally-derived intracellular architectures, including chromosome organization, the endoplasmic reticulum (ER) and spatially distinct ribosome populations. We implement a hybrid stochastic–deterministic framework in which gene expression is modeled using a reaction–diffusion master equation that enforces locality (i.e., reactions occur only when molecules are in physical proximity), while metabolic and transport processes are captured by ordinary differential equations. Guided by electron microscopy and biochemical constraints, we quantify how accounting for intracellular spatial organization alters regulatory predictions in the galactose switch. We show that in present model chromosome geometry has little effect on Gal2p output, whereas ER-associated translation reduces Gal2p delivery to the plasma membrane; the largest decrease of Gal2p abundance occurs when translation of GAL2 mRNA is restricted to a population of ribosomes physically bound to the ER. Together, these results demonstrate that more realistic 3D cellular architectures and local reaction rules can qualitatively change regulatory predictions, motivating integration of intracellular organization in future whole-cell models. Author summary: Eukaryotic cells are highly organized spaces with distinct subcellular compartments and heterogeneous distributions of molecules which influence how cells function. Yet, most computational models of gene regulation assume a spatially homogeneous intracellular environment. To quantify how intracellular architecture influences regulatory predictions, we developed spatially resolved models of the galactose switch in budding yeast, a well-characterized gene regulatory system controlling the response to extracellular galactose. We compared conventional well-stirred simulations with models that explicitly incorporate experimentally informed intracellular organization, including chromosome positioning, endoplasmic reticulum geometry, and functionally distinct ribosome populations. Incorporating these spatial features substantially altered the dynamics of predicted gene activity, protein production, and intracellular sugar levels. Our results demonstrate that the three-dimensional organization of eukaryotic cells can significantly change regulatory outcomes of computational models, underscoring the need for integrating realistic spatial architectures in future models of eukaryotic gene regulation.", "abstract_shown": true, "affiliations": [ "Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.", "National Science Foundation Science and Technology Center for Quantitative Cell Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.", "Molecular Systems Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.", "Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.", "Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.", "Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.", "Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.", "Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America." ], "article_type": "Research Article", "arxiv": null, "author_total": 7, "authors": [ { "affs": [ 0, 1 ], "name": "Tianyu Wu", "orcid": "0009-0000-1436-6167" }, { "affs": [ 1, 2 ], "name": "Marie-Christin Spindler" }, { "affs": [ 3 ], "name": "Abner T Apsley" }, { "affs": [ 4 ], "name": "Emmy Earnest" }, { "affs": [ 3, 5 ], "name": "Zane R Thornburg" }, { "affs": [ 1, 2, 6 ], "name": "Julia Mahamid", "orcid": "0000-0001-6968-041X" }, { "affs": [ 0, 1, 7 ], "name": "Zaida Luthey-Schulten", "orcid": "0000-0001-9749-8367" } ], "bibtex": "https://research.draconitic.com/paper/ba9vwgevadnsg.bib", "cited_by": 0, "doi": "10.1371/journal.pcbi.1014811", "fulltext_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014811", "id": "ba9vwgevadnsg", "issns": [ "1553-7358", "1553-734X" ], "landing_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014811", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Gene Regulatory Network Analysis" ], [ "plos", "/Biology and life sciences/Biochemistry/Biochemical simulations" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Messenger RNA" ], [ "plos", "/Biology and life sciences/Biochemistry/Ribosomes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cell membranes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Cell membranes/Membrane proteins" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Ribosomes" ], [ "plos", "/Biology and life sciences/Computational biology/Biochemical simulations" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Protein translation" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Fungi/Yeast/Saccharomyces/Saccharomyces cerevisiae" ], [ "plos", "/Physical sciences/Chemistry/Chemical compounds/Organic compounds/Carbohydrates/Monosaccharides/Galactose" ], [ "plos", "/Physical sciences/Chemistry/Organic chemistry/Organic compounds/Carbohydrates/Monosaccharides/Galactose" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Saccharomyces cerevisiae" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Yeast and fungal models/Saccharomyces cerevisiae" ], [ "plos", "/Research and analysis methods/Model organisms/Saccharomyces cerevisiae" ] ], "openalex": "W7220375290", "pdf_url": "https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1014811&type=printable", "pmcid": "PMC13705588", "pmid": "42832589", "published": "2026-10-05", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/ba9vwgevadnsg.ris", "sources": [ { "first_seen": "2026-10-30T12:17:37Z", "native_id": "10.1371/journal.pcbi.1014811", "source": "plos", "url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014811" }, { "first_seen": "2026-10-30T12:18:10Z", "native_id": "MED:42832589", "source": "europepmc", "url": "https://europepmc.org/article/MED/42832589" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" } ], "title": "Spatially resolved reaction–diffusion modeling reveals effects of intracellular spatial heterogeneity on yeast galactose network dynamics", "title_text": "Spatially resolved reaction–diffusion modeling reveals effects of intracellular spatial heterogeneity on yeast galactose network dynamics", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:10Z", "url": "https://research.draconitic.com/paper/ba9vwgevadnsg", "venue": "PLOS Computational Biology", "versions": [] }