Cited by 49Down syndrome and intellectual disability researchGenetics and Neurodevelopmental DisordersPluripotent Stem Cells Research

Human iPSC-derived Down syndrome astrocytes display genome-wide perturbations in gene expression, an altered adhesion profile, and increased cellular dynamics

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Ponroy Bally, Blandine, Farmer, W Todd, Jones, Emma V, Jessa, Selin, Kacerovsky, J Benjamin, Mayran, Alexandre, Peng, Huashan, Lefebvre, Julie L +4 more·2020·Human Molecular Genetics

Abstract

Down syndrome (DS), caused by the triplication of human chromosome 21, leads to significant alterations in brain development and is a major genetic cause of intellectual disability. While much is known about changes to neurons in DS, the effects of trisomy 21 on non-neuronal cells such as astrocytes are poorly understood. Astrocytes are critical for brain development and function, and their alteration may contribute to DS pathophysiology. To better understand the impact of trisomy 21 on astrocytes, we performed RNA-sequencing on astrocytes from newly produced DS human induced pluripotent stem cells (hiPSCs). While chromosome 21 genes were upregulated in DS astrocytes, we found consistent up- and down-regulation of genes across the genome with a strong dysregulation of neurodevelopmental, cell adhesion and extracellular matrix molecules. ATAC (assay for transposase-accessible chromatin)-seq also revealed a global alteration in chromatin state in DS astrocytes, showing modified chromatin accessibility at promoters of cell adhesion and extracellular matrix genes. Along with these transcriptomic and epigenomic changes, DS astrocytes displayed perturbations in cell size and cell spreading as well as modifications to cell-cell and cell-substrate recognition/adhesion, and increases in cellular motility and dynamics. Thus, triplication of chromosome 21 is associated with genome-wide transcriptional, epigenomic and functional alterations in astrocytes that may contribute to altered brain development and function in DS.

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  • Co-culture with T21 iPSC-derived astrocytes reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission.

    “Co-culture with T21 iPSC-derived astrocytes also reduces the intrinsic excitability of neurons and tends to have a consequent impact on synaptic development and transmission82,135,145.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [145]

    The Introduction reports that Down syndrome astrocytes affect neuronal synaptic markers, and the discussion suggests that the observed adhesion changes may have implications for synaptogenesis. But this paper does not report that co-culture with its T21 iPSC-derived astrocytes reduces neurons’ intrinsic excitability or alters synaptic transmission. Reduced excitability appears only in the title of a different study listed in its References. (LLM, conf=0.82)

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  • DS iPSC-derived astrocytes have changes in cell adhesion and motility dynamics.

    “Astrocytes differentiated from iPSCs derived from individuals with DS had changes in cell adhesion and motility dynamics compared to matched euploid controls (Bally et al., 2020).”

    From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Bally et al., 2020

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Authors
Ponroy Bally, B., Farmer, W. T., Jones, E. V., Jessa, S., Kacerovsky, J. B., Mayran, A., Peng, H., Lefebvre, J. L., Drouin, J., Hayer, A., Ernst, C., & Murai, K. K.
Affiliations
  • Department of Neurology & Neurosurgery, Brain Repair and Integrative Neuroscience Program, Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montreal, QC H3G 1A4, Canada
  • McGill University Health Centre (CA)
  • Montreal Clinical Research Institute (CA)
  • Douglas Mental Health University Institute (CA)
  • University of Toronto (CA)
  • McGill University (CA)
Corresponding author
Murai, Keith K
Venue
Human Molecular Genetics
Published
2020-01-15
Volume
29
Issue
5
Pages
785-802
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2999698688
Cited by
49
References
112
Citations by year
2026: 6 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 6
FWCI
5.62
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research (OGB 111152, PJT148569, 156247)
  • Natural Sciences and Engineering Research Council of Canada (408044-2011, 69404, 05831-2018)
  • Canada Research Chairs
  • Brain Canada
  • Weston Foundation
  • Sandra and Alain Bouchard Intellectual Disability Research Program
  • McGill Faculty of Medicine
  • Canada First Research Excellence Fund
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
Down syndrome, astrocytes, induced pluripotent stem cells, gene expression dysregulation, chromatin accessibility, cell adhesion, extracellular matrix, cell motility, intellectual disability, brain development
MeSH terms
Astrocytes, Cell Adhesion, Cell Differentiation, Cell Movement, Down Syndrome, Gene Expression Regulation, Humans, Genome, Human, Induced Pluripotent Stem Cells, Neural Stem Cells, Transcriptome

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