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  Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Ziller, M. J., Ortega, J. A., Quinlan, K. A., Santos, D. P., Gu, H., Martin, E. J., et al. (2018). Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology. Cell Stem Cell, 22, 1-16. doi:10.1016/j.stem.2018.02.012.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-DFEB-D Version Permalink: http://hdl.handle.net/21.11116/0000-0000-DFEC-C
Genre: Journal Article

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 Creators:
Ziller, Michael J., Author
Ortega, Juan A. , Author
Quinlan, Katharina A. , Author
Santos, David P. , Author
Gu, Hongcang , Author
Martin , Eric J. , Author
Galonska, Christina1, Author              
Pop, Ramona, Author
Maidl, Susanne , Author
Pardo, Alba Di , Author
Huang , Mei , Author
Meltzer, Herbert Y. , Author
Gnirke , Andreas , Author
Heckman, C. J., Author
Meissner, Alexander1, Author              
Kiskinis, Evangelos , Author
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1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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 Abstract: The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNAme machinery. We quantitatively dissect the role of DNAme in directing somatic cell fate with high-resolution genome-wide bisulfite-, bulk-, and single-cell-RNA sequencing. We find defects in neuralization and MN differentiation in DNMT3A knockouts (KO) that can be rescued by the targeting of DNAme to key developmental loci using catalytically inactive dCas9. We also find decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a list of DNMT3A-regulated targets and a mechanistic link between de novo DNAme, cellular differentiation, and human MN function.

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Language(s): eng - English
 Dates: 2018-02-232018-03-152018-04-05
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.stem.2018.02.012
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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 22 Sequence Number: - Start / End Page: 1 - 16 Identifier: ISSN: 1934-5909
CoNE: /journals/resource/1934-5909