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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 (\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    ) 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\u2013deterministic framework in which gene expression is modeled using a reaction\u2013diffusion 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\n                    <jats:italic>GAL2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014811","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:55:46Z","timestamp":1791222946000},"page":"e1014811","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatially resolved reaction\u2013diffusion modeling reveals effects of intracellular spatial heterogeneity on yeast galactose network dynamics"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1436-6167","authenticated-orcid":true,"given":"Tianyu","family":"Wu","sequence":"first","affiliation":[{"name":"University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"],"department":["Center for Biophysics and Quantitative Biology"]},{"name":"National Science Foundation Science and Technology Center for Quantitative Cell Biology, University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christin","family":"Spindler","sequence":"additional","affiliation":[{"name":"National Science Foundation Science and Technology Center for Quantitative Cell Biology, University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"]},{"name":"European Molecular Biology Laboratory","place":["Heidelberg, Germany"],"department":["Molecular Systems Biology Unit"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abner T.","family":"Apsley","sequence":"additional","affiliation":[{"name":"Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign","place":["Urbana, Illinois, United States of America"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmy","family":"Earnest","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"],"department":["Department of Physics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zane R.","family":"Thornburg","sequence":"additional","affiliation":[{"name":"Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign","place":["Urbana, Illinois, United States of America"]},{"name":"University of Illinois at Urbana-Champaign","place":["Urbana, Illinois, United States of America"],"department":["Cancer Center at Illinois"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-041X","authenticated-orcid":true,"given":"Julia","family":"Mahamid","sequence":"additional","affiliation":[{"name":"National Science Foundation Science and Technology Center for Quantitative Cell Biology, University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"]},{"name":"European Molecular Biology Laboratory","place":["Heidelberg, Germany"],"department":["Molecular Systems Biology Unit"]},{"name":"European Molecular Biology Laboratory","place":["Heidelberg, Germany"],"department":["Cell Biology and Biophysics Unit"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9749-8367","authenticated-orcid":true,"given":"Zaida","family":"Luthey-Schulten","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"],"department":["Center for Biophysics and Quantitative Biology"]},{"name":"National Science Foundation Science and Technology Center for Quantitative Cell Biology, University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"]},{"name":"University of Illinois at Urbana\u2013Champaign","place":["Urbana, Illinois, United States of America"],"department":["Department of Chemistry"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"pcbi.1014811.ref001","volume-title":"Molecular biology of the cell","author":"B Alberts","year":"2015","edition":"6"},{"issue":"5","key":"pcbi.1014811.ref002","article-title":"Visualizing intracellular organelle and cytoskeletal interactions at nanoscale resolution on millisecond timescales","volume":"175","author":"Y 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