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Neurobiol Dis. 2019 Dec;132:104583. doi: 10.1016/j.nbd.2019.104583. Epub 2019 Aug 21.

Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment.

Author information

1
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Box 815, 751 08 Uppsala, Sweden. Electronic address: jens.schuster@igp.uu.se.
2
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Box 815, 751 08 Uppsala, Sweden.
3
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
4
Wallenberg long-term Bioinformatics Support, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
5
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Box 815, 751 08 Uppsala, Sweden. Electronic address: niklas.dahl@igp.uu.se.

Abstract

Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the α-subunit of the neuronal sodium channel Nav1.1. The syndrome is characterized by age-related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Nav1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic inter-neuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Nav1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

KEYWORDS:

Chromatin architecture; Dravet syndrome; Na(v)1.1; Neural differentiation; Neurodevelopment; SCN1A; iPSC

PMID:
31445158
DOI:
10.1016/j.nbd.2019.104583
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