Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine.

BACKGROUND

Mismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we quantified genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2 (Msh2) mice months before tumor onset.

RESULTS

Histone H3 methylation increases in Msh2 compared to control Msh2 mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2 mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2 mice 4 weeks after a single-radiation hit, whereas radiation of Msh2 mice left their histone methylation profiles almost unchanged.

CONCLUSIONS

MMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage.