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

Maria Herberg; Susann Siebert; Marianne Quaas; Torsten Thalheim; Karen Rother; Michelle Hussong; Janine Altmüller; Christiane Kerner; Joerg Galle; Michal R Schweiger; Gabriela Aust

doi:10.1186/s13148-019-0639-8

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

Clin Epigenetics. 2019 Apr 27;11(1):65. doi: 10.1186/s13148-019-0639-8.

Authors

Maria Herberg¹, Susann Siebert^{2

3}, Marianne Quaas^{1

4}, Torsten Thalheim¹, Karen Rother^{4

5}, Michelle Hussong^{2

6}, Janine Altmüller⁷, Christiane Kerner⁴, Joerg Galle¹, Michal R Schweiger^{2

6}, Gabriela Aust⁸

Affiliations

¹ Interdisciplinary Center for Bioinformatics (IZBI), Leipzig University, Leipzig, Germany.
² Laboratory for Translational Epigenetics and Tumor Genetics, University Hospital Cologne, Cologne, Germany.
³ Graduate School for Biological Sciences (GSfBS), University of Cologne, Cologne, Germany.
⁴ Department of Surgery, Research Laboratories, Leipzig University, Liebigstr. 19, D-04103, Leipzig, Germany.
⁵ Laboratory for Clinical and Experimental Hepatology (LCEHep) Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.
⁶ Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
⁷ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
⁸ Department of Surgery, Research Laboratories, Leipzig University, Liebigstr. 19, D-04103, Leipzig, Germany. gabriela.aust@medizin.uni-leipzig.de.

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 VCMsh2^LoxP/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.

Keywords: Histone H3 methylation; Intestine; Mismatch repair deficiency; Msh2; Radiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Case-Control Studies
Chromatin Immunoprecipitation Sequencing
Disease Models, Animal
Epigenesis, Genetic / radiation effects
Female
Gene Regulatory Networks / radiation effects*
Histones / metabolism*
Humans
Intestinal Neoplasms / etiology*
Intestinal Neoplasms / genetics
Intestines / chemistry
Intestines / radiation effects*
Male
Mice
MutS Homolog 2 Protein / genetics*
Whole Genome Sequencing

Substances

Histones
MSH2 protein, human
MutS Homolog 2 Protein