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Genes 2018, 9(1), 17; https://doi.org/10.3390/genes9010017

Linking DNA Damage and Age-Related Promoter DNA Hyper-Methylation in the Intestine

Interdisciplinary Centre for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany
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Received: 20 November 2017 / Revised: 21 December 2017 / Accepted: 21 December 2017 / Published: 5 January 2018
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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Abstract

Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model of intestinal crypts enabling simulation of aberrant DNA and histone methylation of gene promoters during aging. We assume histone state-dependent activity of de novo DNA methyltransferases (DNMTs) and methylation-dependent binding of maintenance DNMTs to CpGs. We simulate aging with and without repeated DNA repair. Motivated by recent findings on the histone demethylase KDM2b, we consider that DNA repair is associated with chromatin opening and improved recruitment of de novo DNMTs. Our results suggest that methylation-dependent binding of maintenance DNMTs to CpGs, establishing bistable DNA methylation states, is a prerequisite to promoter hyper-methylation following DNA repair. With this, the transient increase in de novo DNMT activity during repair can induce switches from low to high methylation states. These states remain stable after repair, leading to an epigenetic drift. The switches are most frequent in genes with H3K27me3 modified promoters. Our model provides a mechanistic explanation on how even successful DNA repair might confer long term changes of the epigenome. View Full-Text
Keywords: intestinal stem cell aging; computational modeling; promoter hyper-methylation; DNA damage repair; epigenetic states intestinal stem cell aging; computational modeling; promoter hyper-methylation; DNA damage repair; epigenetic states
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Thalheim, T.; Herberg, M.; Galle, J. Linking DNA Damage and Age-Related Promoter DNA Hyper-Methylation in the Intestine. Genes 2018, 9, 17.

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