Thalheim, Torsten ORCID: 0000-0001-5489-7405, Hopp, Lydia, Herberg, Maria, Siebert, Susann, Kerner, Christiane, Quaas, Marianne, Schweiger, Michal R., Aust, Gabriela and Galle, Joerg (2020). Fighting Against Promoter DNA Hyper-Methylation: Protective Histone Modification Profiles of Stress-Resistant Intestinal Stem Cells. Int. J. Mol. Sci., 21 (6). BASEL: MDPI. ISSN 1422-0067

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thalheim, TorstenUNSPECIFIEDorcid.org/0000-0001-5489-7405UNSPECIFIED
Hopp, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herberg, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siebert, SusannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerner, ChristianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quaas, MarianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aust, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galle, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-342044
DOI: 10.3390/ijms21061941
Journal or Publication Title: Int. J. Mol. Sci.
Volume: 21
Number: 6
Date: 2020
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1422-0067
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HUMANS LONG-TERM; RADIATION-EXPOSURE; BLOOD LEUKOCYTES; CHROMATIN STATE; HYPERMETHYLATION; DAMAGE; LGR5; H3; HOMEOSTASIS; APOPTOSISMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34204

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