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

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.