Hypomethylation of LINE-1 elements—a key epigenetic marker—characterizes both the inflammatory response in coeliac disease and its associated cancer, small bowel adenocarcinoma, according to a recent study providing new insights into the molecular mechanisms underlying autoimmune disorders and cancer development, while pointing to the potential reversibility of these epigenetic changes through dietary intervention.
LINE-1 (long interspersed nuclear element-1) retrotransposons make up nearly 17% of the human genome. These mobile DNA sequences are tightly regulated by epigenetic mechanisms such as DNA methylation to maintain genomic stability. Hypomethylation of LINE-1 has been implicated in cancer, autoimmune diseases, and other disorders due to its association with genomic instability and inflammation.
In coeliac disease (CeD), an immune-mediated condition triggered by dietary gluten, researchers observed that LINE-1 hypomethylation is a hallmark of the inflammatory response in the small intestine. The study also found this epigenetic signature extends to small bowel adenocarcinomas (SBAs) associated with CeD, suggesting a link between chronic inflammation and cancer risk.
In the study, published in The Journal of Pathology, researchers analyzed LINE-1 methylation levels in 88 SBA cases, including those associated with CeD, Crohn’s disease (CrD), and sporadic occurrences (S-SBAs). They also examined duodenal samples from untreated and treated CeD patients (UCD and TCD, respectively). Key findings include:
- LINE-1 Hypomethylation in CeD and CeD-SBAs: LINE-1 hypomethylation was significantly more pronounced in CeD-associated SBAs compared to CrD-SBAs, S-SBAs, and healthy controls.
- Reversibility with Gluten-Free Diet (GFD): In TCD patients adhering to a strict GFD, LINE-1 methylation levels were partially restored, highlighting the potential for dietary intervention to mitigate epigenetic alterations.
- Inflammatory Gene Expression: CeD-SBAs exhibited a gene expression profile akin to untreated CeD mucosae, with marked upregulation of genes involved in inflammation and T-cell activity.
Interestingly, despite hypomethylation, the LINE-1 elements did not show increased expression of their functional components (ORF1 and ORF2) in most cases, suggesting that the immune microenvironment might suppress LINE-1 activity.
The study positions LINE-1 hypomethylation as a reversible feature of CeD-associated inflammation, rather than a direct driver of cancer. This challenges prior assumptions that hypomethylation invariably leads to retrotransposition and malignancy.
Moreover, the co-occurrence of LINE-1 hypomethylation and MLH1 hypermethylation in CeD-SBAs provides clues about the epigenetic interplay that contributes to cancer risk in chronic inflammatory conditions.
These findings pave the way for further research into the role of LINE-1 hypomethylation in autoimmune diseases and cancer. Potential avenues include exploring its utility as a biomarker for disease activity or cancer risk in CeD patients and developing therapies targeting epigenetic modifications.
The authors declared no conflicts of interest.
