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Epigenetic Gatekeeping of Intestinal Stem Cell Transformation
Alireza Lorzadeh1, Sweta Sharma1, Geroge Ye1
1Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, CA, USA.
Biorxiv : the Preprint Server for Biology
|February 12, 2026
Summary
Epigenetic marks, specifically H3K27me3, act as a barrier against intestinal tumors by maintaining stem cell properties. Loss of this mark in cancer cells allows fetal gene reactivation and tumor growth, explaining treatment resistance.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- Adult intestinal stem cells retain limited cell plasticity, contributing to tumor initiation and relapse.
- Epigenetic mechanisms maintaining stemness and restricting fetal gene expression in adults, and their loss in tumors, remain unclear.
- Tumorigenesis involves non-stem cells potentially replenishing cancer stem cells after targeted therapies.
Purpose of the Study:
- Investigate the epigenetic features governing reversible stemness in adult intestinal crypt cells.
- Determine the role of H3K27ac and H3K27me3 in maintaining stem-cell properties and restricting fetal gene expression.
- Elucidate how epigenetic rewiring, including H3K27me3 loss, contributes to intestinal tumorigenesis and therapy resistance.
Main Methods:
- Analysis of H3K27ac and H3K27me3 marks at enhancers in normal and tumor intestinal cells.
- Utilizing *Apc-/-* mouse models with constitutive Wnt activity to study tumorigenesis.
- Investigating the impact of accelerated or preserved H3K27me3 loss on stemness-related enhancers and tumor progression.
- Examining DNA demethylation at superenhancer domains in tumor growth.
Main Results:
- Reversible stemness in normal adult intestinal cells depends on a balance between H3K27ac and H3K27me3 marks.
- Loss of H3K27me3 at enhancers transforms intestinal stem cells, reactivates fetal genes, and promotes tumor growth.
- H3K27me3 loss erases distinctions between stem and non-stem cells, conferring stemness and contributing to therapy resistance.
- Human colorectal cancers exhibit similar epigenetic rewiring, with H3K27me3 loss correlating with tumor progression.
Conclusions:
- H3K27me3 at Wnt-responsive enhancers is a critical barrier to intestinal tumorigenesis.
- Aberrant reactivation of hundreds of fetal genes is driven by H3K27me3 loss during transformation.
- Understanding this epigenetic regulation offers insights into cancer stem cell targeting and therapeutic resistance.
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