We do see AP-1 go up and nuclear receptors like HNF and PPAR go down in colitis-associated adenomas though. So their oppositional nature seems somewhat similar to the program described and to be amplified following colitis.

The answer is a bit mixed. We see a lot of these fetal/embryonic programs get activated during injury (particularly in the healing phases) but they don’t seem to be remembered following tissue recovery. Rather, the role of AP-1 in non-neoplastic memory seems to be maintaining a more mature program

That’s right. For generally measuring the clonality of different features, we did it across all clones. There’s some analysis in the Extended Data showing differences between the conditions. Thanks!

We’d like to thank our collaborators in the Yilmaz and Breault labs, and PROSPECT @cancerresearchuk.org / NCI for their support. Find out about binding partners, drugging AP-1, the new tools we made and more here at our pre-print: tinyurl.com/ColitisNagar... (14/14)

With rates of early onset colon cancer and IBD rising, our findings also create opportunities for novel diagnostics to track cancer risk (tracking epigenetic memory in stool?) and nominate therapeutic targets development to prevent malignancy (AP-1 inhibition?). (13/14)

We find a central role for the AP-1 in oncogenic memory of inflammation. Given the diversity of processes regulated by this family, we suspect that diverse environmental factors (diet, infection, aging) may all accumulate through this pathway to influence tissue health. (12/14)

Our findings suggest a new model, where:
- Chronic inflammation creates heritable and clonal epigenetic memory
- This primes stem cells for increased expression of pro-proliferative programs
- Therefore, lowering the threshold for oncogenesis once a mutation occurs. (11/14)

Spatial RNA-seq on >200 individual tumors revealed that epigenetic memory of colitis primes tumors for higher AP-1 associated gene expression. Again, we find a remarkably similar proportion of tumors with high activation and that also show additional oncogenic programs. (10/14)

Looking at the earliest stages of microscopic tumor formation, we found that epigenetic memory promoted initial tumor outgrowth. This suggested that grossly larger tumors occurred due to the clustering of many microscopic tumors in close proximity to one another. (9/14)

What about cancer? We induced adenoma formation via APC loss after recovery from colitis. 🚨Colitis-recovered mice developed significantly larger tumors than controls🚨. However, we didn’t see any differences in proliferation or initiation. So why are they bigger? (8/14)

We found a subset of clones to display exceptionally strong memory of inflammation, resembling what we saw in vivo with stem cells. This raises an intriguing possibility that colitis selectively expands certain stem cell populations with altered epigenetic states. (7/14)

To study this further, we developed SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility, and clonal history in single cells. This enabled us to find that epigenetic memory is propagated through clonal lineages. (6/14)

We next asked whether this memory was stored in the stem cells themselves. Using an ex vivo organoid culture system, we found this epigenetic memory to be cell-intrinsic and promote growth. Colitis-derived organoids were both larger and hyperproliferative. (5/14)

Once inflammation resolved and the epithelium healed, gene expression returned to normal (>97% of genes). However, we found that stem cells stored an “epigenetic memory” of damage in their chromatin! Highlighted by a cumulative increase in AP-1 motif accessibility. (4/14)

We focused on one of the most well-established connections - ulcerative colitis and colorectal cancer. Using a mouse model of colitis, we performed SHARE-seq to track chromatin accessibility and gene expression in single cells over the course of disease and recovery. (3/14)

How does inflammation fuel cancer? Chronic inflammation has long been connected to cancer, but the molecular mechanisms are unclear. We hypothesized that inflammation and damage create lasting epigenetic alterations in stem cells, reducing the threshold for oncogenesis. (2/14)