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bioRxiv · 10.64898/2026.01.31.702974

Epigenetic Gatekeeping of Intestinal Stem Cell Transformation

Lorzadeh, A.·Sharma, S.·Ye, G.·Rabaya, S.·Kang, Y. J.·Shivdasani, R.·Jadhav, U.
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Abstract

Widespread cell plasticity recognized in fetal intestinal epithelium is preserved in limited fashion in Wnt-responsive adult stem cells and contributes to tumour initiation, progression, and relapse. It is unclear which epigenetic features maintain stem-cell properties, restrict adult expression of fetal genes, and are attenuated in tumours, allowing non-stem cells to replenish targeted tumour stem cells. Here we show that reversible stemness in normal adult intestinal crypt cells hinges on a dynamic balance between activating H3K27ac and repressive H3K27me3 marks. Cells that leave the Wnt-rich stem-cell niche normally acquire H3K27me3 at thousands of stemness-associated enhancers. Constitutive tumourigenic Wnt activity transforms Apc-/- intestinal stem cells by gradual erosion of H3K27me3 at select enhancers and extends stem-like properties beyond usual anatomic confines; continued depletion of H3K27me3 reactivates enhancers that control growth and expression of a wider swath of fetal genes than appreciated previously. Subsequent focal DNA demethylation at expanded superenhancer domains is associated with tumour growth. Human colorectal cancers also carry evidence of this epigenetic rewiring. Accelerated H3K27me3 loss in mice hastens, and its preservation delays, activation of stemness-related enhancers, superenhancers, and tumour progression. During transformation, H3K27me3 loss at enhancers erases a crucial distinction between stem and non-stem populations, endowing the latter with stemness and providing an explanation for tumour resistance to cancer stem cell targeting. Thus, H3K27me3 at Wnt-responsive enhancers is an intrinsic barrier to intestinal tumourigenesis and aberrant reactivation of hundreds of fetal genes.

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Lorzadeh, A., Sharma, S., Ye, G., Rabaya, S., Kang, Y. J., Shivdasani, R., Jadhav, U.. 2026-02-03. Epigenetic Gatekeeping of Intestinal Stem Cell Transformation. https://doi.org/10.64898/2026.01.31.702974

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