Origin of the cancer-associated intestinal epigenetic drift

Epigenetic alterations, particularly the DNA methylation (DNAm) drift, represent a conserved hallmark of aging across species, influencing biological processes and disease pathogenesis. Recent studies have characterized different DNAm drifts in mammalian aging, and observed, for some of them, a correlation with cell division or organismal lifestyle. However, the molecular mechanisms driving DNAm drifts during aging are still largely unknown. In this study, we identify and characterize a cancer-associated intestine-specific DNAm drift, that initiates in healthy intestinal stem cells with impaired iron homeostasis, propagating through crypt clonality and crypt fission mechanisms to neighboring cells. Experimental evidence using mouse models and intestinal organoids confirms the cell-intrinsic, non-mitotic nature of ACCA drift. Despite the observed heterogeneity at the CpG level confirming the stochastic component of the epigenetic aging, DNAm patterns at the gene level remain consistent, implicating functional relevance to biological processes such as cancer initiation. Mechanistically, ACCA drift is driven by an impaired TET enzyme activity due to dysregulated iron metabolism, linking cellular metabolism to epigenetic alterations. Insights into the interplay between ACCA drift and colorectal cancer (CRC) suggest a mechanistic basis for DNAm changes observed in CRC, potentially explaining the hypermethylation landscape observed in cancerous tissuess. This study enhances our understanding of epigenetic mechanisms in aging and disease, highlighting potential targets for prevention and early-diagnosis of age-related diseases like CRC.