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

Authors :
Thalheim, Torsten
Hopp, Lydia
Herberg, Maria
Siebert, Susann
Kerner, Christiane
Quaas, Marianne
Schweiger, Michal R.
Aust, Gabriela
Galle, Joerg
Thalheim, Torsten
Hopp, Lydia
Herberg, Maria
Siebert, Susann
Kerner, Christiane
Quaas, Marianne
Schweiger, Michal R.
Aust, Gabriela
Galle, Joerg
Publication Year :
2020

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.

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1364933646
Document Type :
Electronic Resource