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Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions
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.
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 immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Karolinska Inst Solna, Dept Neurosci, Stockholm, Sweden.
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2019 (Engelska)Ingår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, nr 10, s. 7113-7127Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.

Ort, förlag, år, upplaga, sidor
2019. Vol. 56, nr 10, s. 7113-7127
Nyckelord [en]
Down syndrome, Induced pluripotent stem cells (iPSC), Neural differentiation, RNA sequencing, Proteome profiling
Nationell ämneskategori
Neurovetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-395428DOI: 10.1007/s12035-019-1585-3ISI: 000486010800032PubMedID: 30989628OAI: oai:DiVA.org:uu-395428DiVA, id: diva2:1365119
Forskningsfinansiär
Vetenskapsrådet, 2015-02424Vetenskapsrådet, 2015-4870Knut och Alice Wallenbergs StiftelseAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceHjärnfonden, FO2018-0100Tillgänglig från: 2019-10-23 Skapad: 2019-10-23 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: 2020-03-05

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Sobol, MariaKlar, JoakimLaan, LooraSchuster, JensAnnerén, GöranKonzer, AnneMi, JiaBergquist, JonasNordlund, JessicaHoeber, JanHuss, MikaelDahl, Niklas
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