1. Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine
- Author
-
Gabriela Aust, Maria Herberg, Michal R. Schweiger, Michelle Hussong, Janine Altmüller, Marianne Quaas, Susann Siebert, Joerg Galle, Christiane Kerner, Karen Rother, and Torsten Thalheim
- Subjects
0301 basic medicine ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,lcsh:QH426-470 ,DNA repair ,lcsh:Medicine ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,Histone H3 ,Mice ,0302 clinical medicine ,Histone methylation ,Intestinal Neoplasms ,Genetics ,Animals ,Humans ,Gene Regulatory Networks ,Epigenetics ,Molecular Biology ,Genetics (clinical) ,Aged ,Radiation ,biology ,Whole Genome Sequencing ,Research ,lcsh:R ,Methylation ,digestive system diseases ,Intestine ,Msh2 ,Intestines ,lcsh:Genetics ,Disease Models, Animal ,030104 developmental biology ,Histone ,MutS Homolog 2 Protein ,030220 oncology & carcinogenesis ,Case-Control Studies ,biology.protein ,Cancer research ,H3K4me3 ,Chromatin Immunoprecipitation Sequencing ,DNA mismatch repair ,Female ,Histone H3 methylation ,Technology Platforms ,Mismatch repair deficiency ,Developmental Biology - Abstract
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 VCMsh2LoxP/LoxP (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. Electronic supplementary material The online version of this article (10.1186/s13148-019-0639-8) contains supplementary material, which is available to authorized users.
- Published
- 2018