Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment
| Autor: | Feria Hikmet Noraddin, Zhe Jin, Maria Sobol, Loora Laan, Jens Schuster, Joakim Klar, Mikael Huss, Niklas Dahl, Bryndis Birnir, Sergiy V. Korol |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Neurogenesis Induced Pluripotent Stem Cells Neurodevelopment Na(v)1.1 Epilepsies Myoclonic Haploinsufficiency Biology Chromatin remodeling lcsh:RC321-571 Transcriptome 03 medical and health sciences 0302 clinical medicine Neural Stem Cells Dravet syndrome medicine Humans SCN1A GABAergic Neurons lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cells Cultured Early onset Neuronal Plasticity iPSC Nav1.1 Sodium channel Neurosciences Chromatin Assembly and Disassembly medicine.disease Cell biology Chromatin architecture NAV1.1 Voltage-Gated Sodium Channel Oxidative Stress 030104 developmental biology Neurology Refractory epilepsy GABAergic Neural differentiation 030217 neurology & neurosurgery Neurovetenskaper |
| Zdroj: | Neurobiology of Disease, Vol 132, Iss, Pp-(2019) |
| Popis: | Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the a-subunit of the neuronal sodium channel Na(v)1.1. 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 Na(v)1.1 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 interneuronal (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 Na(v)1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies. De tre första författarna delar förstaförfattarskapet. |
| Databáze: | OpenAIRE |
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