Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration
Published version of a preprint
Abstract
Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5 + intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair.
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Emerging evidence suggests that molecular redundancy within chromatin remodeling complexes and homeostatic feedback loops may partially buffer against single-gene loss and dampen the spread of dysregulation.
“Emerging evidence suggests that molecular redundancy within chromatin remodeling complexes and homeostatic feedback loops may partially buffer against single-gene loss and dampen the spread of dysregulation (Rozenfeld et al., 2023; Fink et al., 2024).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Fink et al., 2024
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McGinnis, C. S., Murrow, L. M., & Gartner, Z. J. (2019) · Cell Systems · doi:10.1016/j.cels.2019.03.003 · Cited by 4,521 · see citing works
Deep generative modeling for single-cell transcriptomics
Lopez, R., Regier, J., Cole, M. B., Jordan, M. I., & Yosef, N. (2018) · Nature Methods · doi:10.1038/s41592-018-0229-2 · Cited by 2,530 · see citing works
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Qing, Z., Yin, Z., Chen, B., Rao, Z., Yin, D., Li, D., Lu, Y., Shi, M., Li, S., Xu, Y., et al. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1964684
“Emerging evidence suggests that molecular redundancy within chromatin remodeling complexes and homeostatic feedback loops may partially buffer against single-gene loss and dampen the spread of dysregulation (Rozenfeld et al., 2023; Fink et al., 2024).”
- Authors
- Fink, M., Njah, K., Patel, S. J., Cook, D. P., Man, V., Ruso, F., Rajan, A., Narimatsu, M., Obersterescu, A., Pye, M. J., Trcka, D., Chan, K., Ayyaz, A., & Wrana, J. L.
- Affiliations
- Mount Sinai Hospital (CA)
- University of Calgary (CA)
- Corresponding author
- Wrana, Jeffrey L.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2024-11-15
- Volume
- 26
- Issue
- 12
- Pages
- 2084-2098
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W4404391666
- Cited by
- 33
- References
- 2
- Citations by year
- 2026: 19 · 2025: 14
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Cell Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Cancer Society Research Institute (706715)
- Terry Fox Research Institute (PPG#1107)
- Gouvernement du Canada | Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- intestinal regeneration, chromatin remodeling, intestinal stem cells, TGF-beta signaling, Hippo signaling pathway, intestinal crypts, radiation damage, epithelial reprogramming, chromatin accessibility, single-nucleus multiomics, organoids, goblet cells, Paneth cells
- MeSH terms
- Hippo Signaling Pathway, Animals, Cell Differentiation, Intestinal Mucosa, Intestines, Mice, Inbred C57BL, Organoids, Regeneration, Stem Cells, Signal Transduction, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Paneth Cells, Enterocytes, Chromatin Assembly and Disassembly, Receptors, G-Protein-Coupled, Mice, Cellular Reprogramming
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