---
OA_place: publisher
OA_type: hybrid
_id: '22956'
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.
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).
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Cornelia
  full_name: Schwayer, Cornelia
  id: 3436488C-F248-11E8-B48F-1D18A9856A87
  last_name: Schwayer
  orcid: 0000-0001-5130-2226
- first_name: Silvia
  full_name: Barbiero, Silvia
  last_name: Barbiero
- first_name: David
  full_name: Brückner, David
  id: e1e86031-6537-11eb-953a-f7ab92be508d
  last_name: Brückner
  orcid: 0000-0001-7205-2975
- first_name: Koen C.
  full_name: Oost, Koen C.
  last_name: Oost
- first_name: Clara
  full_name: Baader, 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
- first_name: Isa
  full_name: Uccelli, Isa
  last_name: Uccelli
- first_name: Laura
  full_name: Capolupo, Laura
  last_name: Capolupo
- first_name: Ludivine Challet
  full_name: Meylan, Ludivine Challet
  last_name: Meylan
- first_name: Veronique
  full_name: Kalck, Veronique
  last_name: Kalck
- first_name: Franziska
  full_name: Moos, Franziska
  last_name: Moos
- first_name: Simon
  full_name: Suppinger, Simon
  last_name: Suppinger
- first_name: Qiutan
  full_name: Yang, Qiutan
  last_name: Yang
- first_name: Jakob
  full_name: Schnabl, Jakob
  last_name: Schnabl
- first_name: Umut
  full_name: Kilik, Umut
  last_name: Kilik
- first_name: Matthieu
  full_name: Bourdon, Matthieu
  last_name: Bourdon
- first_name: J. Gray
  full_name: Camp, J. Gray
  last_name: Camp
- first_name: Brigitta
  full_name: Stockinger, Brigitta
  last_name: Stockinger
- first_name: Alessandra
  full_name: Ferrari, Alessandra
  last_name: Ferrari
- 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
  full_name: Hannezo, Edouard B
  id: 3A9DB764-F248-11E8-B48F-1D18A9856A87
  last_name: Hannezo
  orcid: 0000-0001-6005-1561
- first_name: Prisca
  full_name: Liberali, Prisca
  last_name: Liberali
citation:
  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>.
  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.
  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.
  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>.
  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.
corr_author: '1'
das_tickbox: '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."
date_created: 2026-09-17T11:06:12Z
date_published: 2026-08-20T00:00:00Z
date_updated: 2026-10-01T08:42:00Z
day: '20'
ddc:
- '570'
doi: 10.1016/j.cell.2026.06.009
ec_funded: 1
external_id:
  pmid:
  - '42379166'
file:
- access_level: open_access
  checksum: 3ff0f4f8be0e79940ba11b18af318ae3
  content_type: application/pdf
  creator: dernst
  date_created: 2026-10-01T08:34:11Z
  date_updated: 2026-10-01T08:34:11Z
  file_id: '23014'
  file_name: 2026_Cell_Schwayer.pdf
  file_size: 15536364
  relation: main_file
  success: 1
file_date_updated: 2026-10-01T08:34:11Z
fulldoi: https://doi.org/10.1016/j.cell.2026.06.009
has_accepted_license: '1'
intvolume: '       189'
issue: '17'
keyword:
- tissue patterning
- heterogeneity
- mechanics
- intestinal regeneration
- epigenetic competence
- multiscale integration
- modeling
- organoids
- image-based phenotyping
- Yap1
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
page: 5266-5282.e17
pmid: 1
project:
- _id: 34e2a5b5-11ca-11ed-8bc3-b2265616ef0b
  grant_number: ALTF 343-2022
  name: A mechano-chemical theory for stem cell fate decisions in organoid development
- _id: 05943252-7A3F-11EA-A408-12923DDC885E
  call_identifier: H2020
  grant_number: '851288'
  name: Design Principles of Branching Morphogenesis
publication: Cell
publication_identifier:
  eissn:
  - 1097-4172
  issn:
  - 0092-8674
publication_status: published
publisher: Cell Press
quality_controlled: '1'
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: Multiscale integration of tissue and chromatin context converts cell heterogeneity
  into stable intestinal patterning
tmp:
  image: /images/cc_by_nc.png
  legal_code_url: https://creativecommons.org/licenses/by-nc/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
  short: CC BY-NC (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 189
year: '2026'
...
---
OA_place: publisher
OA_type: free access
_id: '10406'
abstract:
- lang: eng
  text: Multicellular organisms develop complex shapes from much simpler, single-celled
    zygotes through a process commonly called morphogenesis. Morphogenesis involves
    an interplay between several factors, ranging from the gene regulatory networks
    determining cell fate and differentiation to the mechanical processes underlying
    cell and tissue shape changes. Thus, the study of morphogenesis has historically
    been based on multidisciplinary approaches at the interface of biology with physics
    and mathematics. Recent technological advances have further improved our ability
    to study morphogenesis by bridging the gap between the genetic and biophysical
    factors through the development of new tools for visualizing, analyzing, and perturbing
    these factors and their biochemical intermediaries. Here, we review how a combination
    of genetic, microscopic, biophysical, and biochemical approaches has aided our
    attempts to understand morphogenesis and discuss potential approaches that may
    be beneficial to such an inquiry in the future.
acknowledgement: The authors would like to thank Feyza Nur Arslan, Suyash Naik, Diana
  Pinheiro, Alexandra Schauer, and Shayan Shamipour for their comments on the draft.
  N.M. is supported by an ISTplus postdoctoral fellowship (H2020 Marie-Sklodowska-Curie
  COFUND Action).
article_processing_charge: No
article_type: original
author:
- first_name: Nikhil
  full_name: Mishra, Nikhil
  id: C4D70E82-1081-11EA-B3ED-9A4C3DDC885E
  last_name: Mishra
  orcid: 0000-0002-6425-5788
- first_name: Carl-Philipp J
  full_name: Heisenberg, Carl-Philipp J
  id: 39427864-F248-11E8-B48F-1D18A9856A87
  last_name: Heisenberg
  orcid: 0000-0002-0912-4566
citation:
  ama: Mishra N, Heisenberg C-PJ. Dissecting organismal morphogenesis by bridging
    genetics and biophysics. <i>Annual Review of Genetics</i>. 2021;55:209-233. doi:<a
    href="https://doi.org/10.1146/annurev-genet-071819-103748">10.1146/annurev-genet-071819-103748</a>
  apa: Mishra, N., &#38; Heisenberg, C.-P. J. (2021). Dissecting organismal morphogenesis
    by bridging genetics and biophysics. <i>Annual Review of Genetics</i>. Annual
    Reviews. <a href="https://doi.org/10.1146/annurev-genet-071819-103748">https://doi.org/10.1146/annurev-genet-071819-103748</a>
  chicago: Mishra, Nikhil, and Carl-Philipp J Heisenberg. “Dissecting Organismal Morphogenesis
    by Bridging Genetics and Biophysics.” <i>Annual Review of Genetics</i>. Annual
    Reviews, 2021. <a href="https://doi.org/10.1146/annurev-genet-071819-103748">https://doi.org/10.1146/annurev-genet-071819-103748</a>.
  ieee: N. Mishra and C.-P. J. Heisenberg, “Dissecting organismal morphogenesis by
    bridging genetics and biophysics,” <i>Annual Review of Genetics</i>, vol. 55.
    Annual Reviews, pp. 209–233, 2021.
  ista: Mishra N, Heisenberg C-PJ. 2021. Dissecting organismal morphogenesis by bridging
    genetics and biophysics. Annual Review of Genetics. 55, 209–233.
  mla: Mishra, Nikhil, and Carl-Philipp J. Heisenberg. “Dissecting Organismal Morphogenesis
    by Bridging Genetics and Biophysics.” <i>Annual Review of Genetics</i>, vol. 55,
    Annual Reviews, 2021, pp. 209–33, doi:<a href="https://doi.org/10.1146/annurev-genet-071819-103748">10.1146/annurev-genet-071819-103748</a>.
  short: N. Mishra, C.-P.J. Heisenberg, Annual Review of Genetics 55 (2021) 209–233.
corr_author: '1'
date_created: 2021-12-05T23:01:41Z
date_published: 2021-08-30T00:00:00Z
date_updated: 2026-06-18T08:39:48Z
day: '30'
ddc:
- '570'
department:
- _id: CaHe
doi: 10.1146/annurev-genet-071819-103748
ec_funded: 1
external_id:
  isi:
  - '000747220900010'
  pmid:
  - '34460295'
fulldoi: https://doi.org/10.1146/annurev-genet-071819-103748
intvolume: '        55'
isi: 1
keyword:
- morphogenesis
- forward genetics
- high-resolution microscopy
- biophysics
- biochemistry
- patterning
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1146/annurev-genet-071819-103748
month: '08'
oa: 1
oa_version: Published Version
page: 209-233
pmid: 1
project:
- _id: 260C2330-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '754411'
  name: ISTplus - Postdoctoral Fellowships
publication: Annual Review of Genetics
publication_identifier:
  eissn:
  - 1545-2948
  issn:
  - 0066-4197
publication_status: published
publisher: Annual Reviews
quality_controlled: '1'
scopus_import: '1'
status: public
title: Dissecting organismal morphogenesis by bridging genetics and biophysics
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 55
year: '2021'
...