[{"tmp":{"short":"CC BY-NC (4.0)","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","image":"/images/cc_by_nc.png"},"corr_author":"1","page":"5266-5282.e17","publication_identifier":{"eissn":["1097-4172"],"issn":["0092-8674"]},"scopus_import":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa":1,"fulldoi":"https://doi.org/10.1016/j.cell.2026.06.009","date_published":"2026-08-20T00:00:00Z","day":"20","title":"Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning","researchdata_availability":"yes","publication":"Cell","type":"journal_article","file":[{"file_id":"23014","date_updated":"2026-10-01T08:34:11Z","file_name":"2026_Cell_Schwayer.pdf","relation":"main_file","creator":"dernst","file_size":15536364,"content_type":"application/pdf","checksum":"3ff0f4f8be0e79940ba11b18af318ae3","access_level":"open_access","success":1,"date_created":"2026-10-01T08:34:11Z"}],"volume":189,"acknowledgement":"We thank the Liberali group, M. Verbeek, and C. Soneson for fruitful discussions; E. Tagliavini for IT support; J. Lüthi for Fractal support; H. Köhler for FACS sorting; T.O. Buchholz for help on cell segmentation; B. Treutlein and A. Xavier da Silveira dos Santos for help with library preparation of single-cell ATAC-seq; M. Garioni for help with mouse salivary organoids; M. Kahnwald for help with human intestinal organoids; M. Lütolf, M. Nikolaev, and O. Mitrofanova for providing material and initial training for microwell experiments; J. Tchorz and V. Orsini for intestinal tissue sections of the YAP1 activator experiment in homeostasis; R. Kageyama for DLL1-Venus-T2A-mCherry mice; J.-F. Spetz for technical assistance; C. Lambert and N. Accart for help with sample preparation; Claudia Flandoli for graphic design of schemes; and Zuzana Nascakova for the graphical abstract. We thank the Foundation Hubrecht Organoid Technology (now Foundation Hubrecht Organoid Biobank, https://www.hubrechtorganoidbiobank.org/) for the duodenal organoid line used in this study (HUB-04-A2-001). We thank C.P. Heisenberg, M. Lütolf, C. Tsiairis, J. Zaugg, G. D’Angelo, L. Giorgetti, S. Arber, and the Liberali group for reading the manuscript. C.S. was supported by the European Molecular Biology Organization (Postdoctoral Fellowship ALTF 660-2020) and the Human Frontier Science Program (HFSP) LT000746/2021-L. D.B.B. was supported by the NOMIS Foundation as a NOMIS fellow, an EMBO Postdoctoral Fellowship (ALTF 343-2022), and the Austrian Academy of Sciences through an APART-MINT Fellowship. B.S. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust (FC001159). This work received funding from ERC to E.H. (grant number 851288) and to P.L. (grant number 758617) and from SNSF (310030_208162 and SNSF ERC TMCG-3_223263).","pmid":1,"dataavailabilitystatement":"All sequencing data have been deposited at the Gene Expression Omnibus (GEO) under accession number GEO: GSE283662.\r\nAnalysis of imaging and sequencing data was developed in the Liberali lab and is available at https://github.com/LiberaliLab/symmetry-breaking-2026. Detailed information on the packages used is provided in the STAR Methods section.\r\nAny additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.","language":[{"iso":"eng"}],"oa_version":"Published Version","_id":"22956","year":"2026","article_type":"original","keyword":["tissue patterning","heterogeneity","mechanics","intestinal regeneration","epigenetic competence","multiscale integration","modeling","organoids","image-based phenotyping","Yap1"],"project":[{"_id":"34e2a5b5-11ca-11ed-8bc3-b2265616ef0b","name":"A mechano-chemical theory for stem cell fate decisions in organoid development","grant_number":"ALTF 343-2022"},{"_id":"05943252-7A3F-11EA-A408-12923DDC885E","name":"Design Principles of Branching Morphogenesis","grant_number":"851288","call_identifier":"H2020"}],"ec_funded":1,"month":"08","publication_status":"published","issue":"17","date_updated":"2026-10-01T08:42:00Z","das_tickbox":"1","date_created":"2026-09-17T11:06:12Z","OA_type":"hybrid","status":"public","OA_place":"publisher","quality_controlled":"1","external_id":{"pmid":["42379166"]},"supplementarymaterial":"yes","author":[{"last_name":"Schwayer","orcid":"0000-0001-5130-2226","id":"3436488C-F248-11E8-B48F-1D18A9856A87","first_name":"Cornelia","full_name":"Schwayer, Cornelia"},{"last_name":"Barbiero","first_name":"Silvia","full_name":"Barbiero, Silvia"},{"id":"e1e86031-6537-11eb-953a-f7ab92be508d","orcid":"0000-0001-7205-2975","last_name":"Brückner","full_name":"Brückner, David","first_name":"David"},{"first_name":"Koen C.","full_name":"Oost, Koen C.","last_name":"Oost"},{"full_name":"Baader, Clara","first_name":"Clara","last_name":"Baader"},{"first_name":"Nicole A.","full_name":"Repina, Nicole A.","last_name":"Repina"},{"first_name":"Jinse","full_name":"Kim, Jinse","last_name":"Kim"},{"first_name":"Oscar E.","full_name":"Diaz, Oscar E.","last_name":"Diaz"},{"last_name":"Uccelli","full_name":"Uccelli, Isa","first_name":"Isa"},{"first_name":"Laura","full_name":"Capolupo, Laura","last_name":"Capolupo"},{"last_name":"Meylan","first_name":"Ludivine Challet","full_name":"Meylan, Ludivine Challet"},{"last_name":"Kalck","first_name":"Veronique","full_name":"Kalck, Veronique"},{"first_name":"Franziska","full_name":"Moos, Franziska","last_name":"Moos"},{"full_name":"Suppinger, Simon","first_name":"Simon","last_name":"Suppinger"},{"last_name":"Yang","full_name":"Yang, Qiutan","first_name":"Qiutan"},{"last_name":"Schnabl","full_name":"Schnabl, Jakob","first_name":"Jakob"},{"full_name":"Kilik, Umut","first_name":"Umut","last_name":"Kilik"},{"last_name":"Bourdon","full_name":"Bourdon, Matthieu","first_name":"Matthieu"},{"first_name":"J. Gray","full_name":"Camp, J. Gray","last_name":"Camp"},{"last_name":"Stockinger","first_name":"Brigitta","full_name":"Stockinger, Brigitta"},{"last_name":"Ferrari","full_name":"Ferrari, Alessandra","first_name":"Alessandra"},{"full_name":"Bühler, Marc","first_name":"Marc","last_name":"Bühler"},{"last_name":"Stadler","full_name":"Stadler, Michael B.","first_name":"Michael B."},{"full_name":"Hannezo, Edouard B","first_name":"Edouard B","id":"3A9DB764-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6005-1561","last_name":"Hannezo"},{"first_name":"Prisca","full_name":"Liberali, Prisca","last_name":"Liberali"}],"intvolume":"       189","doi":"10.1016/j.cell.2026.06.009","ddc":["570"],"citation":{"mla":"Schwayer, Cornelia, et al. “Multiscale Integration of Tissue and Chromatin Context Converts Cell Heterogeneity into Stable Intestinal Patterning.” <i>Cell</i>, vol. 189, no. 17, Cell Press, 2026, p. 5266–5282.e17, doi:<a href=\"https://doi.org/10.1016/j.cell.2026.06.009\">10.1016/j.cell.2026.06.009</a>.","ieee":"C. Schwayer <i>et al.</i>, “Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning,” <i>Cell</i>, vol. 189, no. 17. Cell Press, p. 5266–5282.e17, 2026.","ama":"Schwayer C, Barbiero S, Brückner D, et al. Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning. <i>Cell</i>. 2026;189(17):5266-5282.e17. doi:<a href=\"https://doi.org/10.1016/j.cell.2026.06.009\">10.1016/j.cell.2026.06.009</a>","apa":"Schwayer, C., Barbiero, S., Brückner, D., Oost, K. C., Baader, C., Repina, N. A., … Liberali, P. (2026). Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning. <i>Cell</i>. Cell Press. <a href=\"https://doi.org/10.1016/j.cell.2026.06.009\">https://doi.org/10.1016/j.cell.2026.06.009</a>","chicago":"Schwayer, Cornelia, Silvia Barbiero, David Brückner, Koen C. Oost, Clara Baader, Nicole A. Repina, Jinse Kim, et al. “Multiscale Integration of Tissue and Chromatin Context Converts Cell Heterogeneity into Stable Intestinal Patterning.” <i>Cell</i>. Cell Press, 2026. <a href=\"https://doi.org/10.1016/j.cell.2026.06.009\">https://doi.org/10.1016/j.cell.2026.06.009</a>.","ista":"Schwayer C, Barbiero S, Brückner D, Oost KC, Baader C, Repina NA, Kim J, Diaz OE, Uccelli I, Capolupo L, Meylan LC, Kalck V, Moos F, Suppinger S, Yang Q, Schnabl J, Kilik U, Bourdon M, Camp JG, Stockinger B, Ferrari A, Bühler M, Stadler MB, Hannezo EB, Liberali P. 2026. Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning. Cell. 189(17), 5266–5282.e17.","short":"C. Schwayer, S. Barbiero, D. Brückner, K.C. Oost, C. Baader, N.A. Repina, J. Kim, O.E. Diaz, I. Uccelli, L. Capolupo, L.C. Meylan, V. Kalck, F. Moos, S. Suppinger, Q. Yang, J. Schnabl, U. Kilik, M. Bourdon, J.G. Camp, B. Stockinger, A. Ferrari, M. Bühler, M.B. Stadler, E.B. Hannezo, P. Liberali, Cell 189 (2026) 5266–5282.e17."},"article_processing_charge":"Yes (in subscription journal)","abstract":[{"lang":"eng","text":"Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet how such heterogeneities are integrated with the mechanochemical state of the tissue and stabilized at the chromatin level into stable, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (YAP1). We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable and self-organized tissue architecture."}],"license":"https://creativecommons.org/licenses/by-nc/4.0/","file_date_updated":"2026-10-01T08:34:11Z","has_accepted_license":"1","publisher":"Cell Press"},{"publisher":"Elsevier","has_accepted_license":"1","extern":"1","file_date_updated":"2020-07-14T12:47:50Z","article_processing_charge":"Yes","abstract":[{"text":"Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation.","lang":"eng"}],"license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","ddc":["576"],"citation":{"ista":"Torrini C, Cubero RJ, Dirkx E, Braga L, Ali H, Prosdocimo G, Gutierrez MI, Collesi C, Licastro D, Zentilin L, Mano M, Zacchigna S, Vendruscolo M, Marsili M, Samal A, Giacca M. 2019. Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation. Cell Reports. 27(9), 2759–2771.e5.","short":"C. Torrini, R.J. Cubero, E. Dirkx, L. Braga, H. Ali, G. Prosdocimo, M.I. Gutierrez, C. Collesi, D. Licastro, L. Zentilin, M. Mano, S. Zacchigna, M. Vendruscolo, M. Marsili, A. Samal, M. Giacca, Cell Reports 27 (2019) 2759–2771.e5.","mla":"Torrini, Consuelo, et al. “Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation.” <i>Cell Reports</i>, vol. 27, no. 9, Elsevier, 2019, p. 2759–2771.e5, doi:<a href=\"https://doi.org/10.1016/j.celrep.2019.05.005\">10.1016/j.celrep.2019.05.005</a>.","ieee":"C. Torrini <i>et al.</i>, “Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation,” <i>Cell Reports</i>, vol. 27, no. 9. Elsevier, p. 2759–2771.e5, 2019.","apa":"Torrini, C., Cubero, R. J., Dirkx, E., Braga, L., Ali, H., Prosdocimo, G., … Giacca, M. (2019). Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation. <i>Cell Reports</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.celrep.2019.05.005\">https://doi.org/10.1016/j.celrep.2019.05.005</a>","ama":"Torrini C, Cubero RJ, Dirkx E, et al. Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation. <i>Cell Reports</i>. 2019;27(9):2759-2771.e5. doi:<a href=\"https://doi.org/10.1016/j.celrep.2019.05.005\">10.1016/j.celrep.2019.05.005</a>","chicago":"Torrini, Consuelo, Ryan J Cubero, Ellen Dirkx, Luca Braga, Hashim Ali, Giulia Prosdocimo, Maria Ines Gutierrez, et al. “Common Regulatory Pathways Mediate Activity of MicroRNAs Inducing Cardiomyocyte Proliferation.” <i>Cell Reports</i>. Elsevier, 2019. <a href=\"https://doi.org/10.1016/j.celrep.2019.05.005\">https://doi.org/10.1016/j.celrep.2019.05.005</a>."},"intvolume":"        27","doi":"10.1016/j.celrep.2019.05.005","author":[{"first_name":"Consuelo","full_name":"Torrini, Consuelo","last_name":"Torrini"},{"full_name":"Cubero, Ryan J","first_name":"Ryan J","id":"850B2E12-9CD4-11E9-837F-E719E6697425","orcid":"0000-0003-0002-1867","last_name":"Cubero"},{"last_name":"Dirkx","full_name":"Dirkx, Ellen","first_name":"Ellen"},{"full_name":"Braga, Luca","first_name":"Luca","last_name":"Braga"},{"full_name":"Ali, Hashim","first_name":"Hashim","last_name":"Ali"},{"full_name":"Prosdocimo, Giulia","first_name":"Giulia","last_name":"Prosdocimo"},{"full_name":"Gutierrez, Maria Ines","first_name":"Maria Ines","last_name":"Gutierrez"},{"full_name":"Collesi, Chiara","first_name":"Chiara","last_name":"Collesi"},{"last_name":"Licastro","first_name":"Danilo","full_name":"Licastro, Danilo"},{"last_name":"Zentilin","first_name":"Lorena","full_name":"Zentilin, Lorena"},{"full_name":"Mano, Miguel","first_name":"Miguel","last_name":"Mano"},{"last_name":"Zacchigna","full_name":"Zacchigna, Serena","first_name":"Serena"},{"first_name":"Michele","full_name":"Vendruscolo, Michele","last_name":"Vendruscolo"},{"last_name":"Marsili","first_name":"Matteo","full_name":"Marsili, Matteo"},{"last_name":"Samal","full_name":"Samal, Areejit","first_name":"Areejit"},{"first_name":"Mauro","full_name":"Giacca, Mauro","last_name":"Giacca"}],"external_id":{"pmid":["31141697"]},"quality_controlled":"1","status":"public","date_created":"2019-11-26T22:30:07Z","issue":"9","date_updated":"2021-01-12T08:11:56Z","publication_status":"published","month":"05","keyword":["cardiomyocyte","cell cycle","Cofilin2","cytoskeleton","Hippo","microRNA","regeneration","YAP"],"article_type":"original","_id":"7128","oa_version":"Published Version","year":"2019","language":[{"iso":"eng"}],"pmid":1,"volume":27,"type":"journal_article","file":[{"date_created":"2019-11-26T22:30:43Z","file_size":4650750,"creator":"rcubero","checksum":"c5d855d07263bfec718673385d0ea2d7","access_level":"open_access","content_type":"application/pdf","date_updated":"2020-07-14T12:47:50Z","file_id":"7129","relation":"main_file","file_name":"torrini_cellreports_2019.pdf"}],"publication":"Cell Reports","title":"Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation","day":"28","fulldoi":"https://doi.org/10.1016/j.celrep.2019.05.005","date_published":"2019-05-28T00:00:00Z","oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_identifier":{"issn":["2211-1247"]},"tmp":{"short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"page":"2759-2771.e5"}]