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H3K36 Methylation-regulated Cell Plasticity – The Key to Intestinal Homeostasis and Regeneration?

By Stuart P. Atkinson, Ph.D.

August 26, 2025

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The Importance of Regulating Cell Plasticity

An elevated level of cell plasticity underpins the generation of the diverse types of cells from stem/progenitor cells required to support normal tissue formation and function; however, the maintenance of tissue integrity/function requires the subsequent restriction of cell plasticity following terminal differentiation (Brumbaugh, Stefano, & Hochedlinger and Vierbuchen & Wernig). While a failure to restrict cell plasticity can prompt the development of diseases such as cancer (Hanahan, 2022), specific cell types must be able to regain a level of plasticity following injury/insult to tissues such as the intestine to support regenerative processes (Meyer et al.). As specific gene expression profiles underpin cell plasticity, multiple epigenetic regulatory mechanisms may play critical roles, but which?

A previous Nature Cell Biology study authored by Justin Brumbaugh (University of Colorado) revealed the overall importance of histone H3 lysine 36 (H3K36) methylation to the regulation of lineage-specific gene expression in adult and induced pluripotent stem cells (Brumbaugh et al.). The current paradigm links the presence of H3K36 di- and tri-methylation (H3K36me2 and H3K36me3) at gene regulatory regions to active transcription (Wagner & Carpenter), with this modification profile thought to antagonize Polycomb activity (via PRC2) and the deposition of the transcriptionally repressive histone H3 lysine 27 tri-methylation (H3K27me3) histone modification.

A subsequent study from researchers from the laboratories of Justin Brumbaugh and Peter J. Dempsey (University of Colorado) now explores the epigenetic regulation of cell plasticity, employing the mouse small intestine as a model system and focusing on the importance of H3K36 methylation. The epithelial cells required to ensure intestinal function (Meyer et al.) can dedifferentiate following injury to support intestinal stem cell repopulation and the subsequent production of differentiated cell types that comprise the entire intestinal epithelium (Saxena & Shivdasani); however, the epigenetic mechanisms that intestinal epithelial cells employ to reinforce their differentiated cell identity and function while retaining the capacity to dedifferentiate back into stem cells remained somewhat unknown. Of further interest, intestinal epithelial cells display broad similarity in most epigenetic features, which may lower the barrier to dedifferentiation and explain how cells regain plasticity following injury (Kim et al.). Now, a recent Nature Cell Biology article from Brumbaugh and Dempsey identifies H3K36 methylation as a critical regulatory switch underpinning intestinal epithelial cell plasticity that mediates the balance between specialized cell identity and tissue regeneration (Pashos et al.).

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Cell Plasticity Supported by Dynamic H3K36 Methylation Ensures Cell Identity and Supports Tissue Regeneration

In addition to in vitro studies employing organoids and in vivo studies employing mouse models, Pashos et al. applied a wide range of advanced techniques, including RNA-seq, single-cell RNA-seq, and cleavage under targets and tagmentation (CUT&Tag) to map histone modifications; furthermore, the authors employed an H3K36me2 antibody from Active Motif during the development of this exciting study.

They initially discovered that distinct intestinal epithelial cell types display varying H3K36 methylation profiles, with H3K36me3 preferentially enriched at cell identity-associated genes, and secretory cell types (such as goblet and Paneth cells) exhibiting the most distinct methylation profiles. The selective disruption of the H3K36me2 and H3K36me3 modifications in intestinal epithelial cells allowed the spread of the repressive H3K27me3 modification via the activity of PRC2 in regions that flanked cell identity-associated genes. These epigenetic alterations induced the transcriptional downregulation of associated genes, produced a defect in the Paneth and goblet cell differentiation, and prompted the accumulation of abnormally localized, intermediate secretory progenitor cells. In short, the loss of H3K36 methylation-mediated transcriptional control in intestinal epithelial cells promoted a defect in intestinal homeostasis, with results suggesting the need for H3K36 methylation to reinforce the expression of genes required to maintain intestinal epithelial cell identity by preventing PRC2-mediated silencing.

Interestingly, the authors revealed that suppressing H3K36 methylation in the mouse intestinal epithelium induced a state of cell plasticity characterized by a regenerative gene expression profile. Additionally, irradiating mice or intestinal organoids (consisting of only intestinal epithelial cells) to induce regeneration prompted a transient reduction of H3K36me3 at cell identity-associated genes (allowing PRC2 and H3K27me3 to silence their expression) that resolved following successful regeneration. These findings suggested that besides reinforcing the gene expression profiles required to maintain specialized intestinal epithelial cell identity, the dynamic regulation of H3K36 methylation plays a fundamental role in regulating cell plasticity and tissue regeneration.

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Cell Plasticity and H3K36 Methylation: Where Next?

Overall, these exciting studies, which combine in vivo analyses, organoid generation, and the application of techniques such as RNA-seq and CUT&Tag, suggest that H3K36 methylation regulates tissue function by ensuring robust cell identity and supporting tissue regeneration following injury in the epithelial cells of the mouse intestine. The authors hope to next determine the relevance of the H3K36me2/me3-H3K27me3 interplay at cell identity-associated genes in other tissues, decipher what mechanisms control H3K36me3 deposition near identity-associated genes during homeostasis and regenerative genes during regeneration, and explore the possible interplay between H3K36 methylation and DNA methylation (given the results of recent studies; Ansari et al.). The team also highlighted a recently published study from Hoetker et al., which revealed that H3K36 methylation in mouse embryonic fibroblasts represents a barrier to reprogramming into induced pluripotent stem cells, suggesting that dynamic H3K36 methylation may represent a general mechanism that regulates plasticity during development and homeostasis.

For more on how H3K36 methylation-mediated cell plasticity may represent the regulatory underpinnings of intestinal homeostasis and regeneration, see Nature, January 2025.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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