Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression
| Autor: | Alexander M. Tsankov, Aleksandra Alicja Arczewska, Tarjei S. Mikkelsen, Veronika Akopian, Alex K. Shalek, Zachary D. Smith, Alexander Meissner, Riley S. Drake, Benjamin E. Mead, Samuel J. Allon, Marc H. Wadsworth, Jocelyn Charlton |
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| Rok vydání: | 2018 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Male Methyltransferase Transcription Genetic Entropy Human Embryonic Stem Cells Biology Cell fate determination DNA Methyltransferase 3A 03 medical and health sciences 0302 clinical medicine Humans Epigenetics DNA (Cytosine-5-)-Methyltransferases RNA Messenger Induced pluripotent stem cell Molecular Biology Gene knockout 030304 developmental biology 0303 health sciences Cell Cycle Gene Expression Regulation Developmental Cell Differentiation Methylation DNA Methylation Stem Cells and Regeneration Embryonic stem cell Cell biology Repressor Proteins Enhancer Elements Genetic DNA methylation embryonic structures 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Development |
| ISSN: | 1477-9129 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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