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


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.

SUBMITTER: Tsankov AM 

PROVIDER: S-EPMC6803377 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Tsankov Alexander M AM   Wadsworth Marc H MH   Akopian Veronika V   Charlton Jocelyn J   Allon Samuel J SJ   Arczewska Aleksandra A   Mead Benjamin E BE   Drake Riley S RS   Smith Zachary D ZD   Mikkelsen Tarjei S TS   Shalek Alex K AK   Meissner Alexander A  

Development (Cambridge, England) 20190912 19


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 <i>de novo</i> 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, D  ...[more]

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