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

ABSTRACT: DNA methylation is a well studied, yet still incompletely understood component of the multi-layered epigenome. The somatic DNA methylation landscape is established early in development, but remains highly dynamic within focal regions that tend to overlap with gene regulatory elements. The functional significance of these dynamic changes remains unresolved. Here we utilized a powerful human ESC differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNA methylation machinery to dissect the role of DNA methylation in directing somatic cell fate. We quantitatively and in high-resolution measure the molecular and functional consequences of epigenetic perturbation. We find defects in neuralization and MN development. We also observe decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a specific list of epigenetically deregulated targets and a mechanistic link between de novo DNA methylation, cellular differentiation and human MN function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90553 | GEO | 2018/03/15

REPOSITORIES: GEO

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