---
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
license: https://creativecommons.org/licenses/by-nc/4.0/
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'
...
---
_id: '7128'
abstract:
- lang: eng
  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.
article_processing_charge: Yes
article_type: original
author:
- first_name: Consuelo
  full_name: Torrini, Consuelo
  last_name: Torrini
- first_name: Ryan J
  full_name: Cubero, Ryan J
  id: 850B2E12-9CD4-11E9-837F-E719E6697425
  last_name: Cubero
  orcid: 0000-0003-0002-1867
- first_name: Ellen
  full_name: Dirkx, Ellen
  last_name: Dirkx
- first_name: Luca
  full_name: Braga, Luca
  last_name: Braga
- first_name: Hashim
  full_name: Ali, Hashim
  last_name: Ali
- first_name: Giulia
  full_name: Prosdocimo, Giulia
  last_name: Prosdocimo
- first_name: Maria Ines
  full_name: Gutierrez, Maria Ines
  last_name: Gutierrez
- first_name: Chiara
  full_name: Collesi, Chiara
  last_name: Collesi
- first_name: Danilo
  full_name: Licastro, Danilo
  last_name: Licastro
- first_name: Lorena
  full_name: Zentilin, Lorena
  last_name: Zentilin
- first_name: Miguel
  full_name: Mano, Miguel
  last_name: Mano
- first_name: Serena
  full_name: Zacchigna, Serena
  last_name: Zacchigna
- first_name: Michele
  full_name: Vendruscolo, Michele
  last_name: Vendruscolo
- first_name: Matteo
  full_name: Marsili, Matteo
  last_name: Marsili
- first_name: Areejit
  full_name: Samal, Areejit
  last_name: Samal
- first_name: Mauro
  full_name: Giacca, Mauro
  last_name: Giacca
citation:
  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>
  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>
  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>.
  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.
  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.
  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>.
  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.
date_created: 2019-11-26T22:30:07Z
date_published: 2019-05-28T00:00:00Z
date_updated: 2021-01-12T08:11:56Z
day: '28'
ddc:
- '576'
doi: 10.1016/j.celrep.2019.05.005
extern: '1'
external_id:
  pmid:
  - '31141697'
file:
- access_level: open_access
  checksum: c5d855d07263bfec718673385d0ea2d7
  content_type: application/pdf
  creator: rcubero
  date_created: 2019-11-26T22:30:43Z
  date_updated: 2020-07-14T12:47:50Z
  file_id: '7129'
  file_name: torrini_cellreports_2019.pdf
  file_size: 4650750
  relation: main_file
file_date_updated: 2020-07-14T12:47:50Z
fulldoi: https://doi.org/10.1016/j.celrep.2019.05.005
has_accepted_license: '1'
intvolume: '        27'
issue: '9'
keyword:
- cardiomyocyte
- cell cycle
- Cofilin2
- cytoskeleton
- Hippo
- microRNA
- regeneration
- YAP
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
page: 2759-2771.e5
pmid: 1
publication: Cell Reports
publication_identifier:
  issn:
  - 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte
  proliferation
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 27
year: '2019'
...