Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions
(2019) In Molecular Neurobiology 56(10). p.7113-7127- Abstract
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... (More)
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.
(Less)
- author
- publishing date
- 2019-10
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cell Differentiation/genetics, Cell Proliferation/genetics, Down Syndrome/genetics, Female, Humans, Induced Pluripotent Stem Cells/pathology, Male, Mitochondria/genetics, Models, Biological, Neurites/metabolism, Neurogenesis/genetics, Neurons/metabolism, Proteome/metabolism, RNA, Messenger/genetics, Reactive Oxygen Species/metabolism, Time Factors, Transcription, Genetic, Transcriptome/genetics
- in
- Molecular Neurobiology
- volume
- 56
- issue
- 10
- pages
- 15 pages
- publisher
- Humana Press
- external identifiers
-
- pmid:30989628
- scopus:85064625946
- ISSN
- 1559-1182
- DOI
- 10.1007/s12035-019-1585-3
- language
- English
- LU publication?
- no
- id
- 268cd35a-409d-40bd-a360-321599a07893
- date added to LUP
- 2021-08-09 15:45:44
- date last changed
- 2024-06-16 16:34:20
@article{268cd35a-409d-40bd-a360-321599a07893,
abstract = {{<p>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.</p>}},
author = {{Sobol, Maria and Klar, Joakim and Laan, Loora and Shahsavani, Mansoureh and Schuster, Jens and Annerén, Göran and Konzer, Anne and Mi, Jia and Bergquist, Jonas and Nordlund, Jessica and Hoeber, Jan and Huss, Mikael and Falk, Anna and Dahl, Niklas}},
issn = {{1559-1182}},
keywords = {{Cell Differentiation/genetics; Cell Proliferation/genetics; Down Syndrome/genetics; Female; Humans; Induced Pluripotent Stem Cells/pathology; Male; Mitochondria/genetics; Models, Biological; Neurites/metabolism; Neurogenesis/genetics; Neurons/metabolism; Proteome/metabolism; RNA, Messenger/genetics; Reactive Oxygen Species/metabolism; Time Factors; Transcription, Genetic; Transcriptome/genetics}},
language = {{eng}},
number = {{10}},
pages = {{7113--7127}},
publisher = {{Humana Press}},
series = {{Molecular Neurobiology}},
title = {{Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions}},
url = {{https://lup.lub.lu.se/search/files/101035355/Transcriptome_and_Proteome_Profiling.pdf}},
doi = {{10.1007/s12035-019-1585-3}},
volume = {{56}},
year = {{2019}},
}