Thalheim, Torsten, Siebert, Susann, Quaas, Marianne, Herberg, Maria, Schweiger, Michal R., Aust, Gabriela and Galle, Joerg (2021). Epigenetic Drifts during Long-Term Intestinal Organoid Culture. Cells, 10 (7). BASEL: MDPI. ISSN 2073-4409
Full text not available from this repository.Abstract
Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and accessible to genetic engineering. Thus, they represent an optimal tool for studying the mechanisms of tissue maintenance and aging. Long-term expansion under standard growth conditions, however, is accompanied by changes in the growth pattern and kinetics. As a potential explanation of these alterations, epigenetic drifts in organoid culture have been suggested. Here, we studied histone tri-methylation at lysine 4 (H3K4me3) and 27 (H3K27me3) and transcriptome profiles of intestinal organoids derived from mismatch repair (MMR)-deficient and control mice and cultured for 3 and 20 weeks and compared them with data on their tissue of origin. We found that, besides the expected changes in short-term culture, the organoids showed profound changes in their epigenomes also during the long-term culture. The most prominent were epigenetic gene activation by H3K4me3 recruitment to previously unmodified genes and by H3K27me3 loss from originally bivalent genes. We showed that a long-term culture is linked to broad transcriptional changes that indicate an ongoing maturation and metabolic adaptation process. This process was disturbed in MMR-deficient mice, resulting in endoplasmic reticulum (ER) stress and Wnt activation. Our results can be explained in terms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||||
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URN: | urn:nbn:de:hbz:38-576698 | ||||||||||||||||||||||||||||||||
DOI: | 10.3390/cells10071718 | ||||||||||||||||||||||||||||||||
Journal or Publication Title: | Cells | ||||||||||||||||||||||||||||||||
Volume: | 10 | ||||||||||||||||||||||||||||||||
Number: | 7 | ||||||||||||||||||||||||||||||||
Date: | 2021 | ||||||||||||||||||||||||||||||||
Publisher: | MDPI | ||||||||||||||||||||||||||||||||
Place of Publication: | BASEL | ||||||||||||||||||||||||||||||||
ISSN: | 2073-4409 | ||||||||||||||||||||||||||||||||
Language: | English | ||||||||||||||||||||||||||||||||
Faculty: | Unspecified | ||||||||||||||||||||||||||||||||
Divisions: | Unspecified | ||||||||||||||||||||||||||||||||
Subjects: | no entry | ||||||||||||||||||||||||||||||||
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URI: | http://kups.ub.uni-koeln.de/id/eprint/57669 |
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