Fighting Against Promoter DNA Hyper-Methylation: Protective Histone Modification Profiles of Stress-Resistant Intestinal Stem Cells.

Torsten Thalheim,Susann Siebert,Michal R Schweiger,Joerg Galle,Maria Herberg,Lydia Hopp,Marianne Quaas,Christiane Kerner,Gabriela Aust

doi:10.3390/ijms21061941

Torsten Thalheim, Susann Siebert + Show 7 more

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https://doi.org/10.3390/ijms21061941

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Abstract

Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Recently, we have suggested that promoter DNA hyper-methylation originates in DNA repair and that even successful DNA repair might confer this kind of epigenetic long-term change. Here, we ask for interrelations between promoter DNA methylation and histone modification changes observed in the intestine weeks after irradiation and/or following Msh2 loss. We focus on H3K4me3 recruitment to the promoter of H3K27me3 target genes. By RNA- and histone ChIP-sequencing, we demonstrate that this recruitment occurs without changes of the average gene transcription and does not involve H3K9me3. Applying a mathematical model of epigenetic regulation of transcription, we show that the recruitment can be explained by stronger DNA binding of H3K4me3 and H3K27me3 histone methyl-transferases as a consequence of lower DNA methylation. This scenario implicates stable transcription despite of H3K4me3 recruitment, in agreement with our RNA-seq data. Following several kinds of stress, including moderate irradiation, stress-sensitive intestinal stem cell (ISCs) are known to become replaced by more resistant populations. Our simulation results suggest that the stress-resistant ISCs are largely protected against promoter hyper-methylation of H3K27me3 target genes.

Highlights

Our epigenome is subject to age-related changes, among them are alterations of DNA methylation
We considered that DNA repair is associated with chromatin opening and improved recruitment of de novo DNA methyltransferases (DNMTs) [11,12]
We focus on H3K27me3 target genes that were observed to recruit H3K4me3 after irradiation and/or loss of Msh2 in the intestine, that is, under genomic stress [20]

Summary

Introduction

Our epigenome is subject to age-related changes, among them are alterations of DNA methylation. Two antagonistic trends have been identified: an overall DNA hypo-methylation and a hyper-methylation of a subgroup of gene promoters [1]. While these changes are common and used to predict biological age [2,3,4], the mechanisms behind these changes are still not fully understood. The nucleosomes, which are associated with them, carry a tri-methylation at lysine 27 of histone H3 (H3K27me). The nucleosomes, which are associated with them, carry a tri-methylation at lysine 27 of histone H3 (H3K27me3) This modification is associated with gene silencing [7]

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Conclusion