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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 University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.ORCID iD: 0000-0003-4185-7409
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Karolinska Inst Solna, Dept Neurosci, Stockholm, Sweden.
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2019 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7113-7127Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2019. Vol. 56, no 10, p. 7113-7127
Keywords [en]
Down syndrome, Induced pluripotent stem cells (iPSC), Neural differentiation, RNA sequencing, Proteome profiling
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-395428DOI: 10.1007/s12035-019-1585-3ISI: 000486010800032PubMedID: 30989628OAI: oai:DiVA.org:uu-395428DiVA, id: diva2:1365119
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2015-4870Knut and Alice Wallenberg FoundationAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Swedish Brain Foundation, FO2018-0100Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved

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