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DNA methylation changes during long-term in vitro cell culture are caused by epigenetic drift

Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes. We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated during long-term culture of mesenchymal stem cells (MSCs) and other cell types. Bisulfite barcoded amplicon seque...

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Main Authors: Franzen, Julia (Author) , Georgomanolis, Theodoros (Author) , Selich, Anton (Author) , Kuo, Chao-Chung (Author) , Stöger, Reinhard (Author) , Brant, Lilija (Author) , Mulabdić, Melita Sara (Author) , Fernandez-Rebollo, Eduardo (Author) , Grezella, Clara (Author) , Ostrowska, Alina (Author) , Begemann, Matthias (Author) , Nikolić, Miloš (Author) , Rath, Björn (Author) , Ho, Anthony Dick (Author) , Rothe, Michael (Author) , Schambach, Axel (Author) , Papantonis, Argyris (Author) , Wagner, Wolfgang (Author)
Format: Article (Journal)
Language:English
Published: 19 May 2021
In: Communications biology
Year: 2021, Volume: 4, Pages: 1-12
ISSN:2399-3642
DOI:10.1038/s42003-021-02116-y
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s42003-021-02116-y
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s42003-021-02116-y
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Author Notes:Julia Franzen, Theodoros Georgomanolis, Anton Selich, Chao-Chung Kuo, Reinhard Stöger, Lilija Brant, Melita Sara Mulabdić, Eduardo Fernandez-Rebollo, Clara Grezella, Alina Ostrowska, Matthias Begemann, Miloš Nikolić, Björn Rath, Anthony D. Ho, Michael Rothe, Axel Schambach, Argyris Papantonis & Wolfgang Wagner
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Summary:Culture expansion of primary cells evokes highly reproducible DNA methylation (DNAm) changes. We have identified CG dinucleotides (CpGs) that become continuously hyper- or hypomethylated during long-term culture of mesenchymal stem cells (MSCs) and other cell types. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development and without association to oligoclonal subpopulations. Circularized chromatin conformation capture (4C) revealed reproducible changes in nuclear organization between early and late passages, while there was no enriched interaction with other genomic regions that also harbor culture-associated DNAm changes. Chromatin immunoprecipitation of CTCF did not show significant differences during long-term culture of MSCs, however culture-associated hypermethylation was enriched at CTCF binding sites and hypomethylated CpGs were devoid of CTCF. Taken together, our results support the notion that DNAm changes during culture-expansion are not directly regulated by a targeted mechanism but rather resemble epigenetic drift.
Item Description:Gesehen am 16.08.2021
Physical Description:Online Resource
ISSN:2399-3642
DOI:10.1038/s42003-021-02116-y

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