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  Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression

Tsankov, A. M., Wadsworth, M. H., Akopian, V., Charlton, J., Allon, S. J., Arczewska, A. A., et al. (2019). Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression. Development, 2019: 146. doi:10.1242/dev.174722.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-CFE6-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-CFE7-F
Genre: Journal Article

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Tsankow_2019.pdf (Publisher version), 6MB
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© 2019. Published by The Company of Biologists Ltd
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 Creators:
Tsankov, Alexander M. , Author
Wadsworth, Marc H. , Author
Akopian, Veronika , Author
Charlton, Jocelyn1, Author              
Allon, Samuel J. , Author
Arczewska, Aleksandra Alicja1, Author              
Mead, Benjamin E. , Author
Drake, Riley S. , Author
Smith, Zachary D. , Author
Mikkelsen, Tarjei S. , Author
Shalek, Alex K. , Author
Meissner, Alexander1, Author              
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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Free keywords: DNA methylation, DNA methyltransferases,Pluripotency, Single-cell RNA-sequencing
 Abstract: Maintenance of pluripotency and specification towards a new cell fate are both dependent on precise interactions between extrinsic signals and transcriptional and epigenetic regulators. Directed methylation of cytosines by the de novo methyltransferases DNMT3A and DNMT3B plays an important role in facilitating proper differentiation, whereas DNMT1 is essential for maintaining global methylation levels in all cell types. Here, we generated single-cell mRNA expression data from wild-type, DNMT3A, DNMT3A/3B and DNMT1 knockout human embryonic stem cells and observed a widespread increase in cellular and transcriptional variability, even with limited changes in global methylation levels in the de novo knockouts. Furthermore, we found unexpected transcriptional repression upon either loss of the de novo methyltransferase DNMT3A or the double knockout of DNMT3A/3B that is further propagated upon differentiation to mesoderm and ectoderm. Taken together, our single-cell RNA-sequencing data provide a high-resolution view into the consequences of depleting the three catalytically active DNMTs in human pluripotent stem cells.

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Language(s): eng - English
 Dates: 2018-12-072019-09-12
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1242/dev.174722
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Title: Development
  Other : Development
Source Genre: Journal
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Publ. Info: Cambridge, Cambridgeshire : Company of Biologists
Pages: - Volume / Issue: 2019 Sequence Number: 146 Start / End Page: - Identifier: ISSN: 0950-1991
CoNE: https://pure.mpg.de/cone/journals/resource/954927546241