Epigenetic memory of colitis promotes tumour growth
Article metadata
Article Date: 25 March 2026
Article URL: https://www.nature.com/articles/s41586-026-10258-4
Article Image: (not provided)
Summary
This Nature paper shows that repeated intestinal inflammation leaves a durable epigenetic ‘memory’ in colonic stem cells that persists long after tissue recovery and makes tumours grow faster once oncogenic mutations occur. Using a mouse DSS colitis model, single-cell joint chromatin and transcriptome profiling (SHARE-seq) and a clonal lineage extension (SHARE-TRACE), the authors find that chronic injury increases chromatin accessibility at AP-1 transcription-factor (FOS/JUN) sites, that a minority of stem-cell clones acquire especially strong AP-1-associated epigenetic states, and that these states are clonally inherited and maintained through DNA methylation changes. FOX family factors (notably FOXP1/FOXA1) stabilise AP-1 binding. Mice recovered from colitis develop larger early adenomas after APC loss, and short-term AP-1 inhibition during tumour initiation reduces this enhanced growth, implicating AP-1 activity as a mediator of the pro-tumour effect of epigenetic memory.
The study combines in vivo tissue profiling, ex vivo organoids, biochemistry (in vitro TF cobinding assays), whole-genome methylation and spatial transcriptomics to link chronic inflammation, clonal epigenetic change and accelerated early tumour outgrowth.
Key Points
- Chronic colitis causes persistent changes to chromatin accessibility in colonic stem cells despite histological recovery; AP-1 motif sites show increased accessibility that can last >100 days.
- Single-cell joint ATAC–RNA profiling (SHARE-seq) identifies an AP-1-high subpopulation (~10% of stem cells) with a regenerative/proliferative program (P20) enriched after colitis.
- Clonal lineage tracing (SHARE-TRACE) shows epigenetic states — notably AP-1 accessibility — are heritable within clones, producing epigenetically primed clonal fields.
- DNA methylation changes negatively correlate with accessibility changes, suggesting durable ‘epi-mutations’ underlie the memory and are not erased by transient TF inhibition.
- FOX transcription factors (FOXP1/FOXA1) cooperate with and stabilise AP-1 binding at composite sites; biochemical assays and deep-learning footprinting support this cooperativity.
- After APC loss, colitis-recovered mice develop larger microscopic tumours and a greater fraction of tumours with high AP-1/P20 expression; short-term AP-1 inhibition during initiation reduces tumour growth selectively in colitis-recovered mice.
- The data support a model of epigenetic field effects: clusters of clonally expanded, epigenetically primed stem cells lower the threshold for malignant outgrowth following oncogenic hits.
- Implication: epigenetic signatures of inflammatory memory could be diagnostic markers of cancer risk and potential therapeutic targets to prevent malignancy after chronic inflammatory disease.
Why should I read this?
Because if you care about how long-term inflammation actually turns into cancer, this paper is a neat, data-rich route-map. It shows inflammation doesn’t just leave scars — it rewires stem-cell epigenomes in ways that stick around, get passed down the line and speed up tumour growth later. If you’re working on IBD, cancer risk, epigenetics or TF biology, they’ve done the heavy lifting so you don’t have to read dozens of scattered studies.
Author note (style)
Punchy take: this is a high-impact, mechanistic study that ties chronic inflammation to heritable epigenetic change and enhanced early tumour expansion. The finding that AP-1 and FOX factors create a clonally propagated pro‑regenerative state with oncogenic consequences is both conceptually important and actionable — especially because short-term AP-1 blockade during initiation blunted the effect.