[{"ddc":["570"],"OA_type":"hybrid","date_published":"2026-08-20T00:00:00Z","has_accepted_license":"1","fulldoi":"https://doi.org/10.1016/j.cell.2026.06.009","article_type":"original","keyword":["tissue patterning","heterogeneity","mechanics","intestinal regeneration","epigenetic competence","multiscale integration","modeling","organoids","image-based phenotyping","Yap1"],"tmp":{"name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","short":"CC BY-NC (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","image":"/images/cc_by_nc.png"},"OA_place":"publisher","date_updated":"2026-10-01T08:42:00Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","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."}],"ec_funded":1,"file_date_updated":"2026-10-01T08:34:11Z","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.","external_id":{"pmid":["42379166"]},"issue":"17","file":[{"success":1,"file_id":"23014","date_created":"2026-10-01T08:34:11Z","file_size":15536364,"file_name":"2026_Cell_Schwayer.pdf","checksum":"3ff0f4f8be0e79940ba11b18af318ae3","access_level":"open_access","relation":"main_file","creator":"dernst","content_type":"application/pdf","date_updated":"2026-10-01T08:34:11Z"}],"intvolume":"       189","_id":"22956","researchdata_availability":"yes","status":"public","oa_version":"Published Version","day":"20","das_tickbox":"1","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).","year":"2026","citation":{"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.","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>","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.","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>.","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.","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>."},"publisher":"Cell Press","publication_identifier":{"issn":["0092-8674"],"eissn":["1097-4172"]},"pmid":1,"title":"Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning","oa":1,"doi":"10.1016/j.cell.2026.06.009","type":"journal_article","corr_author":"1","scopus_import":"1","publication":"Cell","author":[{"full_name":"Schwayer, Cornelia","last_name":"Schwayer","id":"3436488C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5130-2226","first_name":"Cornelia"},{"first_name":"Silvia","last_name":"Barbiero","full_name":"Barbiero, Silvia"},{"orcid":"0000-0001-7205-2975","first_name":"David","last_name":"Brückner","id":"e1e86031-6537-11eb-953a-f7ab92be508d","full_name":"Brückner, David"},{"first_name":"Koen C.","last_name":"Oost","full_name":"Oost, Koen C."},{"first_name":"Clara","full_name":"Baader, Clara","last_name":"Baader"},{"full_name":"Repina, Nicole A.","last_name":"Repina","first_name":"Nicole A."},{"first_name":"Jinse","last_name":"Kim","full_name":"Kim, Jinse"},{"last_name":"Diaz","full_name":"Diaz, Oscar E.","first_name":"Oscar E."},{"full_name":"Uccelli, Isa","last_name":"Uccelli","first_name":"Isa"},{"first_name":"Laura","full_name":"Capolupo, Laura","last_name":"Capolupo"},{"full_name":"Meylan, Ludivine Challet","last_name":"Meylan","first_name":"Ludivine Challet"},{"last_name":"Kalck","full_name":"Kalck, Veronique","first_name":"Veronique"},{"full_name":"Moos, Franziska","last_name":"Moos","first_name":"Franziska"},{"first_name":"Simon","full_name":"Suppinger, Simon","last_name":"Suppinger"},{"full_name":"Yang, Qiutan","last_name":"Yang","first_name":"Qiutan"},{"first_name":"Jakob","last_name":"Schnabl","full_name":"Schnabl, Jakob"},{"last_name":"Kilik","full_name":"Kilik, Umut","first_name":"Umut"},{"first_name":"Matthieu","last_name":"Bourdon","full_name":"Bourdon, Matthieu"},{"last_name":"Camp","full_name":"Camp, J. Gray","first_name":"J. Gray"},{"full_name":"Stockinger, Brigitta","last_name":"Stockinger","first_name":"Brigitta"},{"last_name":"Ferrari","full_name":"Ferrari, Alessandra","first_name":"Alessandra"},{"first_name":"Marc","full_name":"Bühler, Marc","last_name":"Bühler"},{"first_name":"Michael B.","full_name":"Stadler, Michael B.","last_name":"Stadler"},{"first_name":"Edouard B","orcid":"0000-0001-6005-1561","id":"3A9DB764-F248-11E8-B48F-1D18A9856A87","last_name":"Hannezo","full_name":"Hannezo, Edouard B"},{"first_name":"Prisca","last_name":"Liberali","full_name":"Liberali, Prisca"}],"supplementarymaterial":"yes","date_created":"2026-09-17T11:06:12Z","article_processing_charge":"Yes (in subscription journal)","project":[{"grant_number":"ALTF 343-2022","name":"A mechano-chemical theory for stem cell fate decisions in organoid development","_id":"34e2a5b5-11ca-11ed-8bc3-b2265616ef0b"},{"name":"Design Principles of Branching Morphogenesis","_id":"05943252-7A3F-11EA-A408-12923DDC885E","call_identifier":"H2020","grant_number":"851288"}],"quality_controlled":"1","page":"5266-5282.e17","language":[{"iso":"eng"}],"volume":189,"publication_status":"published","month":"08"},{"status":"public","_id":"22510","oa_version":"None","day":"01","das_tickbox":"1","citation":{"chicago":"Kim, Jongho, M. Chase Dwelle, Stephanie K. Kampf, Simone Fatichi, and Valeriy Y. Ivanov. “On the Non-Uniqueness of the Hydro-Geomorphic Responses in a Zero-Order Catchment with Respect to Soil Moisture.” <i>Advances in Water Resources</i>. Elsevier, 2016. <a href=\"https://doi.org/10.1016/j.advwatres.2016.03.019\">https://doi.org/10.1016/j.advwatres.2016.03.019</a>.","mla":"Kim, Jongho, et al. “On the Non-Uniqueness of the Hydro-Geomorphic Responses in a Zero-Order Catchment with Respect to Soil Moisture.” <i>Advances in Water Resources</i>, vol. 92, Elsevier, 2016, pp. 73–89, doi:<a href=\"https://doi.org/10.1016/j.advwatres.2016.03.019\">10.1016/j.advwatres.2016.03.019</a>.","short":"J. Kim, M.C. Dwelle, S.K. Kampf, S. Fatichi, V.Y. Ivanov, Advances in Water Resources 92 (2016) 73–89.","ista":"Kim J, Dwelle MC, Kampf SK, Fatichi S, Ivanov VY. 2016. On the non-uniqueness of the hydro-geomorphic responses in a zero-order catchment with respect to soil moisture. Advances in Water Resources. 92, 73–89.","ama":"Kim J, Dwelle MC, Kampf SK, Fatichi S, Ivanov VY. On the non-uniqueness of the hydro-geomorphic responses in a zero-order catchment with respect to soil moisture. <i>Advances in Water Resources</i>. 2016;92:73-89. doi:<a href=\"https://doi.org/10.1016/j.advwatres.2016.03.019\">10.1016/j.advwatres.2016.03.019</a>","apa":"Kim, J., Dwelle, M. C., Kampf, S. K., Fatichi, S., &#38; Ivanov, V. Y. (2016). On the non-uniqueness of the hydro-geomorphic responses in a zero-order catchment with respect to soil moisture. <i>Advances in Water Resources</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.advwatres.2016.03.019\">https://doi.org/10.1016/j.advwatres.2016.03.019</a>","ieee":"J. Kim, M. C. Dwelle, S. K. Kampf, S. Fatichi, and V. Y. Ivanov, “On the non-uniqueness of the hydro-geomorphic responses in a zero-order catchment with respect to soil moisture,” <i>Advances in Water Resources</i>, vol. 92. Elsevier, pp. 73–89, 2016."},"year":"2016","publisher":"Elsevier","intvolume":"        92","date_updated":"2026-08-06T07:50:36Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","abstract":[{"text":"This study advances mechanistic interpretation of predictability challenges in hydro-geomorphology related to the role of soil moisture spatial variability. Using model formulations describing the physics of overland flow, variably saturated subsurface flow, and erosion and sediment transport, this study explores (1) why a basin with the same mean soil moisture can exhibit distinctly different spatial moisture distributions, (2) whether these varying distributions lead to non-unique hydro-geomorphic responses, and (3) what controls non-uniqueness in relation to the response type. Two sets of numerical experiments are carried out with two physically-based models, HYDRUS and tRIBS+VEGGIE+FEaST, and their outputs are analyzed with respect to pre-storm moisture state. The results demonstrate that distinct spatial moisture distributions for the same mean wetness arise because near-surface soil moisture dynamics exhibit different degrees of coupling with deeper-soil moisture and the process of subsurface drainage. The consequences of such variations are different depending on the type of hydrological response. Specifically, if the predominant runoff response is of infiltration excess type, the degree of non-uniqueness is related to the spatial distribution of near-surface moisture. If runoff is governed by subsurface stormflow, the extent of deep moisture contributing area and its “readiness to drain” determine the response characteristics. Because the processes of erosion and sediment transport superimpose additional controls over factors governing runoff generation and overland flow, non-uniqueness of the geomorphic response can be highly dampened or enhanced. The explanation is sediment composed by multi-size particles can alternate states of mobilization or surface shielding and the transient behavior is inherently intertwined with the availability of mobile particles. We conclude that complex nonlinear dynamics of hydro-geomorphic processes are inherent expressions of physical interactions. As complete knowledge of watershed properties, states, or forcings will always present the ultimate, if ever resolvable, challenge, deterministic predictability will remain handicapped. Coupling of uncertainty quantification methods and space-time physics-based approaches will need to evolve to facilitate mechanistic interpretations and informed practical applications.","lang":"eng"}],"date_published":"2016-07-01T00:00:00Z","OA_type":"closed access","fulldoi":"https://doi.org/10.1016/j.advwatres.2016.03.019","article_type":"original","keyword":["Soil moisture","Spatial heterogeneity","Hydrological response","Geomorphic response","Non-uniqueness","Hydraulic connectivity"],"page":"73-89","language":[{"iso":"eng"}],"volume":92,"publication_status":"published","month":"07","date_created":"2026-07-27T12:30:24Z","article_processing_charge":"No","quality_controlled":"1","scopus_import":"1","publication":"Advances in Water Resources","author":[{"last_name":"Kim","full_name":"Kim, Jongho","first_name":"Jongho"},{"first_name":"M. Chase","last_name":"Dwelle","full_name":"Dwelle, M. Chase"},{"full_name":"Kampf, Stephanie K.","last_name":"Kampf","first_name":"Stephanie K."},{"full_name":"Fatichi, Simone","last_name":"Fatichi","id":"cf8e546b-a9b0-11f0-a43b-aa89ed1b56d6","first_name":"Simone"},{"full_name":"Ivanov, Valeriy Y.","last_name":"Ivanov","first_name":"Valeriy Y."}],"publication_identifier":{"issn":["0309-1708"]},"title":"On the non-uniqueness of the hydro-geomorphic responses in a zero-order catchment with respect to soil moisture","doi":"10.1016/j.advwatres.2016.03.019","type":"journal_article","extern":"1"}]