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Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.ORCID-id: 0000-0002-4383-9880
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.ORCID-id: 0000-0003-4185-7409
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.ORCID-id: 0000-0002-4717-1558
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2019 (Engelska)Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 132, artikel-id 104583Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
ACADEMIC PRESS INC ELSEVIER SCIENCE , 2019. Vol. 132, artikel-id 104583
Nyckelord [en]
Dravet syndrome, SCN1A, Na(v)1.1, iPSC, Neural differentiation, Neurodevelopment, Chromatin architecture
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-398427DOI: 10.1016/j.nbd.2019.104583ISI: 000497252500015PubMedID: 31445158OAI: oai:DiVA.org:uu-398427DiVA, id: diva2:1375951
Forskningsfinansiär
Vetenskapsrådet, 2015-02424Vetenskapsrådet, 2015-02417Knut och Alice Wallenbergs StiftelseAstraZenecaHjärnfonden, FO2018-0100Hjärnfonden, FO2019-0210Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
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De tre första författarna delar förstaförfattarskapet.

Tillgänglig från: 2019-12-06 Skapad: 2019-12-06 Senast uppdaterad: 2019-12-09Bibliografiskt granskad
Ingår i avhandling
1. Induced pluripotent stem cell (iPSC) modelling for the identification of mechanisms behind neurodevelopmental disorders
Öppna denna publikation i ny flik eller fönster >>Induced pluripotent stem cell (iPSC) modelling for the identification of mechanisms behind neurodevelopmental disorders
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Human induced pluripotent stem cells (iPSCs) have opened new possibilities to recapitulate disease mechanisms and to model disorders in vitro. In the studies presented here, iPSCs were established to model neural differentiation in Down syndrome (DS), caused by trisomy for chromosome 21 (T21); Dravet syndrome (DRS), caused by variants in the SCN1A gene; and an ataxia syndrome, caused by a variant in the NFASC gene. The major aim has been to uncover molecular and cellular mechanisms behind perturbed neurogenesis in the three disorders.

In Paper I, the analysis of transcriptomes and proteomes of the DS iPSC derived neural model revealed several perturbed gene clusters with strong temporal dynamics along neural differentiation, markedly down-regulated mitochondrial genes and a dysregulation of hub proteins. These results predict complex and genome-wide changes in T21 neural cells associated with prolonged cell cycle, reduced cell growth and a perturbed energy metabolism.

In Paper II, it was demonstrated that the transcriptional profile of iPSC based neural model system for DS was enriched for differentially methylated genes and gene families when compared to a corresponding euploid model. The differentially methylated genes were enriched for transcriptional regulation and chromatin structure, suggesting novel mechanistic links between the genomic imbalance caused by T21 and the global transcriptional dysregulation in DS.

 In Paper III, it was shown that DRS patient iPSCs differentiated into GABAergic interneurons exhibit a dysregulated epilepsy gene network as well as an altered expression of genes involved in chromatin remodelling, accompanied by abnormal electrophysiological properties and increased stress sensitivity.

In Paper IV, it was shown that neural iPSCs, established from a patient with an ataxia syndrome and a novel homozygous variant in the NFASC gene, lack a full-length neurofascin-186 important for cell adhesion. The patient derived neural iPSCs showed delayed neuronal differentiation, reduced sprouting, shorter neurites and altered electrophysiology.

The Papers I-IV show that patient derived neural iPSCs enable to identify molecular and cellular mechanisms associated with neuropathogenesis. Besides specific dysregulated pathways and cellular defects in models of three developmental disorders, with shortlists of novel candidate disease biomarkers, the results are consistent with prior data and clinical presentation of patients. The knowledge gained is of paramount importance for translation into clinical settings and a step towards development of novel therapies with the ultimate goal to alleviate symptoms of affected individuals.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2020. s. 63
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1622
Nyckelord
Induced pluripotent stem cells, Neurogenesis, Neural differentiation, Down syndrome, Dravet syndrome, Ataxia
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Medicinsk cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-398620 (URN)978-91-513-0833-3 (ISBN)
Disputation
2020-02-07, Room A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2020-01-17 Skapad: 2019-12-09 Senast uppdaterad: 2020-01-17

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Schuster, JensLaan, LooraKlar, JoakimJin, ZheKorol, SergiyNoraddin, Feria HikmetSobol, MariaBirnir, BryndisDahl, Niklas
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Science for Life Laboratory, SciLifeLabMedicinsk genetik och genomikBirnir: Molekylär fysiologi och neurovetenskapKlinisk och experimentell patologi
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