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We approached this problem for neuroepithelial development of human pluripotent stem cells\u00a0(differentiation variable), in the presence or absence of valproic acid (signaling variable). Using few basic assumptions (sequential differentiation states of cells; discrete on\/off states for individual genes in these states), and time-resolved transcriptome data, a comprehensive model of spontaneous and perturbed gene expression dynamics was developed. The model made reliable predictions (average correlation of 0.85 between predicted and subsequently tested expression values). Even regulations predicted to be non-monotonic were successfully validated by PCR in new sets of experiments. Transient patterns of gene regulation were identified from model predictions. They pointed towards activation of Wnt signaling as a candidate pathway leading to a redirection of differentiation away from neuroepithelial cells towards neural crest. Intervention experiments, using a Wnt\/beta-catenin antagonist, led to a phenotypic rescue of this disturbed differentiation. Thus, our broadly applicable model allows the analysis of transcriptome changes in complex time\/perturbation matrices.<\/jats:p>","DOI":"10.1093\/nar\/gkaa1089","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T12:47:48Z","timestamp":1603802868000},"page":"12577-12592","source":"Crossref","is-referenced-by-count":16,"title":["Kinetic modeling of stem cell transcriptome dynamics to identify regulatory modules of normal and disturbed neuroectodermal differentiation"],"prefix":"10.1093","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5288-9118","authenticated-orcid":false,"given":"Johannes","family":"Meisig","sequence":"first","affiliation":[{"name":"Institute of Pathology, Charit\u00e9-Universit\u00e4tsmedizin, 10117 Berlin, Germany"},{"name":"IRI Life Sciences, Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Dreser","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Chair foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Kapitza","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Chair foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margit","family":"Henry","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Neurophysiology, University of Cologne, 50931 Cologne,\u00a0Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Rotshteyn","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Neurophysiology, University of Cologne, 50931 Cologne,\u00a0Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Rahnenf\u00fchrer","sequence":"additional","affiliation":[{"name":"Department of Statistics, TU Dortmund University, 44221 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan\u00a0G","family":"Hengstler","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agapios","family":"Sachinidis","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Neurophysiology, University of Cologne, 50931 Cologne,\u00a0Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Waldmann","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Chair foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[{"name":"In Vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Chair foundation, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0171-7447","authenticated-orcid":false,"given":"Nils","family":"Bl\u00fcthgen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Charit\u00e9-Universit\u00e4tsmedizin, 10117 Berlin, Germany"},{"name":"IRI Life Sciences, Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"2020121502535922100_B1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nature07287","article-title":"An intrinsic mechanism of corticogenesis from embryonic stem cells","volume":"455","author":"Gaspard","year":"2008","journal-title":"Nature"},{"key":"2020121502535922100_B2","doi-asserted-by":"crossref","first-page":"e6286","DOI":"10.1371\/journal.pone.0006286","article-title":"Neural differentiation of embryonic stem cells in vitro: a road map to neurogenesis in the embryo","volume":"4","author":"Abranches","year":"2009","journal-title":"PLoS One"},{"key":"2020121502535922100_B3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.conb.2009.12.001","article-title":"Mechanisms of neural specification from embryonic stem cells","volume":"20","author":"Gaspard","year":"2010","journal-title":"Curr. 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