Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome
Open accessAbstract
Background: Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Ca v 1.2. Methods: To identify patient-specific alterations in transcriptome organization, we conducted a genome-wide weighted co-expression network analysis (WGCNA) on neural progenitors and neurons from multiple lines of induced pluripotent stem cells (iPSC) derived from normal and TS (G406R in CACNA1C) individuals. We employed transcription factor binding site enrichment analysis to assess whether TS associated co-expression changes reflect calcium-dependent co-regulation. Results: We identified reproducible developmental and activity-dependent gene co-expression modules conserved in patient and control cell lines. By comparing cell lines from case and control subjects, we also identified co-expression modules reflecting distinct aspects of TS, including intellectual disability and ASD-related phenotypes. Moreover, by integrating co-expression with transcription factor binding analysis, we showed the TS-associated transcriptional changes were predicted to be co-regulated by calcium-dependent transcriptional regulators, including NFAT, MEF2, CREB, and FOXO, thus providing a mechanism by which altered Ca 2+signaling in TS patients leads to the observed molecular dysregulation. Conclusions: We applied WGCNA to construct co-expression networks related to neural development and depolarization in iPSC-derived neural cells from TS and control individuals for the first time. These analyses illustrate how a systems biology approach based on gene networks can yield insights into the molecular mechanisms of neural development and function, and provide clues as to the functional impact of the downstream effects of Ca 2+signaling dysregulation on transcription.
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The systems biology analysis uncovered Ca2+-dependent co-expression modules reflecting distinct aspects of Timothy syndrome, including intellectual disability and ASD-related phenotypes.
“The analysis uncovered Ca2+-dependent co-expression modules that reflect distinct aspects of TS, including intellectual disability and ASD-related phenotypes.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Tian et al., 2014
An unbiased systems biology analysis found that the gene-expression differences in Timothy syndrome were compatible with involvement of known Ca2+-dependent transcriptional regulators including CREB, NFAT, MEF2, and FOXO.
“When subjected to an unbiased systems biology analysis (Tian et al., 2014), the pattern of differences in gene expression was compatible with involvement of known Ca2+-dependent transcriptional regulators, including CREB, NFAT, MEF2, and FOXO.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Tian et al., 2014
Several genes that cause rare forms of autism spectrum disorder regulate expression or splicing of many genes associated with psychiatric disorders.
“Several genes that cause rare forms of ASD (e.g., FMR1, CACNA1C, and TCF4) regulate expression or splicing of many genes associated with psychiatric disorders (Tian et al., 2014; Weyn-Vanhentenryck et al., 2014).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Tian et al., 2014
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- Authors
- Tian, Y., Voineagu, I., Paşca, S. P., Won, H., Chandran, V., Horvath, S., Dolmetsch, R. E., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- UNSW Sydney (AU)
- Stanford University (US)
- Corresponding author
- Geschwind, Daniel H
- ORCID
- Venue
- Genome Medicine
- Published
- 2014-10-10
- Volume
- 6
- Issue
- 10
- Pages
- 75-75
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC4213483
- OpenAlex
- W2028033268
- Cited by
- 93
- References
- 91
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2022: 4 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 13 · 2016: 18 · 2015: 9
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- China Scholarship Council
- National Institutes of Health (5r01mh094714-04)
- National Institute of Mental Health (5R01MH094714, R01-MH094714, R01MH100027, R37MH060233)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- Timothy syndrome, CACNA1C, Cav1.2, L-type calcium channels, iPSC-derived neurons, neural progenitor cells, gene co-expression network, calcium signaling, transcriptional regulation, NFAT, MEF2, CREB, FOXO, autism spectrum disorder, intellectual disability, depolarization, transcription factor binding sites
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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