Epigenetic memory of colitis promotes tumour growth
A mechanistic link between chronic inflammation and malignancy
Introduction
Inflammation is a major risk factor for cancer, but the underlying molecular mechanisms remain unclear. There are well-established clinical associations between inflammation in the gut and cancer and patients with ulcerative colitis (UC) are 2-5x more likely to develop colorectal cancer (CRC).
The epigenome is dynamically regulated as cells respond to environmental challenges, by making new regions of their DNA accessible and active, directing transcription factor (TF) proteins to these sites activating the expression of new genes and cellular functions. The gastrointestinal tract provides a particularly compelling model for studying epigenetic memory due to its continuous and extensive exposure to the environment.
In this recent Nature paper a mouse model of colitis demonstrated that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days and which influences predisposition for cancer.
Main Points
- Colitis in mice was induced by repeated injury to the colon through oral administration of low-dose dextran sodium sulphate (DSS).
- Three disease progression stages were defined; acute injury (one cycle of DSS), chronic injury (three cycles of DSS) and recovery (>21 days or more since the last DSS exposure).
- Genes related to epithelial inflammation were found to be upregulated in stem cells during acute injury.
- Chronic injury further activated genes related to wound healing, cell junction reformation and extracellular matrix reconstruction.
- Following recovery, these changes returned to baseline as well as 97% of the 246 genes transcriptionally activated in stem cells during either stage of disease. However, cells from recovered tissue were found to be epigenomically distinct from cells derived from control tissue.
- To more precisely define this epigenomic memory, TFs were grouped by binding motif sequence similarity, which revealed persistent alterations following recovery, with the most prominent of these being a cumulative gain in accessibility at activator protein 1 (AP-1) motif sites.
- To determine whether cellular memory is clonally heritable and mediated by the epigenome and if the memory of colitis was durably encoded through DNA methylation, the Authors created SHARE-TRACE (SHARE-seq with clonal tracing) to simultaneously measure a cell’s clonal lineage history, gene expression, differentiation state and chromatin accessibility and whole-genome DNA methylation sequencing was also performed.
- The results showed that cellular memory can be maintained within clonal lineages and result in cell populations with exceptionally altered epigenetic states.
- This molecular memory is facilitated by durable changes to chromatin accessibility and DNA methylation.
- Furthermore, the retrieval of these memories coincides with altered morphology and function and are reliant on the binding of AP-1 factors.
- Finally, the Authors showed that recovery from colitis primes stem cells for increased expression of an AP-1 regulated gene program following oncogenic mutation and that AP-1 activity accelerates tumour growth.
Conclusion
The findings in this paper suggest a model whereby chronic inflammation encodes an epigenetic memory of repair in colonic stem cells that promotes tumour growth through progressive gain of AP-1 and tissue-specific TF accessibility at pro-proliferative genes. This memory promotes tumorigenesis by increasing malignant outgrowth once a stem cell acquires an oncogenic mutation, thereby contributing to the raised incidence of cancer associated with chronic inflammation.
Furthermore, by combining single cell epigenomics with lineage tracing, a method and framework was provided to enable quantitative assessment of how such cellular states propagate through stem cell lineages. This could lead to the development of new strategies for erasing pathologic cellular memory, mitigating its maladaptive consequences, offering a promising avenue for disease prevention in patients with cancer and other chronic diseases
EPISTEM SERVICES
Epistem offers several pre-clinical human cancer models (including CRC), and the team also have decades of experience modelling IBD and radiation injury / regeneration. Models of both acute and chronic IBD are available, including the DSS model described in this paper. Key cell populations can be isolated for phenotyping by immuno-labelling techniques and/or short-term culture and functional assays.
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