How Cells in the Intestine Rewrite Their Identity to Heal When Injured

A Tissue That Never Rests: Life Inside the Intestinal Lining

The lining of our intestine is one of the most dynamic tissues in the body. Every few days, it renews itself completely, balancing the need to maintain specialized cell functions while staying flexible enough to repair damage. A recent study reveals that a single epigenetic mark, H3K36 methylation, plays a central role in controlling this balance between identity and regeneration (Meyer et al., 2022). Under healthy conditions, intestinal epithelial cells rely on H3K36 methylation, specifically H3K36me2 and H3K36me3, to stabilize the expression of genes that define mature cell types such as stem cells, goblet cells, and Paneth cells. These marks act as guardians of cellular identity by blocking the spread of the repressive chromatin mark, H3K27me3, into genes required for specialized function. In essence, H3K36 methylation helps cells remember who they are.

H3K36 methylation as a guardian of specialized genes

When injury occurs, such as after radiation damage, this epigenetic landscape changes dramatically. The study shows that H3K36me3 levels drop at genes linked to mature cell identity, while H3K27me3 spreads into those regions, silencing them. At the same time, H3K27me3 is removed from genes associated with regeneration and fetal-like programs, allowing those genes to turn on. This switch enables cells to temporarily abandon their specialized roles and enter a more plastic, regenerative state. Remarkably, this same regenerative gene program appears when H3K36 methylation is experimentally suppressed, even without injury. Cells begin expressing markers of regeneration, such as Clu, and adopt gene expression profiles similar to those seen after tissue damage. Organoids lacking H3K36 methylation regenerate more efficiently after irradiation, suggesting that its loss primes cells for repair.

A molecular switch between stability and plasticity

Mechanistically, the study proposes a dual control system. During homeostasis, H3K36 methylation keeps the Polycomb repressive complex 2 (PRC2) engaged on regenerative genes while protecting cell-type genes. During regeneration, loss of H3K36 methylation redistributes PRC2 away from regenerative genes and toward mature-cell genes, enabling the shift from specialization to plasticity. This work offers a new paradigm for how chromatin modifications regulate tissue repair: regeneration is not just about activating new genes, but about epigenetically silencing old identities. H3K36 methylation acts as a molecular switch, allowing intestinal cells to switch between stability and flexibility as needed. The figure below, taken directly from the paper by Pashos et al., shows how loss of H3K36 methylation prevents normal intestinal cell differentiation. H3K36M is the K36M mutant that cannot be methylated.

Understanding this mechanism sheds light on how tissues heal, how cell identity is preserved, and how epigenetic misregulation contributes to disease. This raises exciting questions about whether similar chromatin-based control systems operate in other regenerative tissues (Pashos et al., 2025).

This story of cellular reinvention is drawn from the work of Alison R. S. Pashos, Anne R. Meyer, Cameron Bussey-Sutton, Erin S. O’Connor, Mariel Coradin, Marilyne Coulombe, Kent A. Riemondy, Sanjana Potlapelly, Brian D. Strahl, Gunnar C. Hansson, Peter J. Dempsey, and Justin Brumbaugh, published in Nature Cell Biology (2025). Their research reveals how epigenetic marks, H3K36 and H3K27 methylation, help intestinal cells decide when to hold onto their identity and when to let go in order to regenerate after injury. By uncovering how chromatin can act as both a lock and a release switch for cell fate, this work reshapes how we think about tissue repair and opens new doors for understanding regeneration, disease, and future therapeutic strategies.

 Abnormal secretory cells emerge after disruption of H3K36 methylation. Healthy intestinal tissue contains clearly defined secretory cell types such as goblet and Paneth cells. In contrast, removing H3K36 methylation leads to the appearance of abnormal secretory cells that no longer resemble their normal counterparts. This visual comparison highlights how a single chemical mark on histones can reshape cellular identity and alter how the intestine responds to stress and injury.

References

Meyer, A.R., M.E. Brown, P.S. McGrath, and P.J. Dempsey. 2022. Injury-Induced Cellular Plasticity Drives Intestinal Regeneration. Cell Mol Gastroenterol Hepatol. 13:843-856.

Pashos, A.R.S., A.R. Meyer, C. Bussey-Sutton, E.S. O'Connor, M. Coradin, M. Coulombe, K.A. Riemondy, S. Potlapelly, B.D. Strahl, G.C. Hansson, P.J. Dempsey, and J. Brumbaugh. 2025. H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium. Nat Cell Biol. 27:202-217.