7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages
Abstract
Cell reprogramming promises to make characterization of the impact of human genetic variation on health and disease experimentally tractable by enabling the bridging of genotypes to phenotypes in developmentally relevant human cell lineages. Here we apply this paradigm to two disorders caused by symmetrical copy number variations of 7q11.23, which display a striking combination of shared and symmetrically opposite phenotypes--Williams-Beuren syndrome and 7q-microduplication syndrome. Through analysis of transgene-free patient-derived induced pluripotent stem cells and their differentiated derivatives, we find that 7q11.23 dosage imbalance disrupts transcriptional circuits in disease-relevant pathways beginning in the pluripotent state. These alterations are then selectively amplified upon differentiation of the pluripotent cells into disease-relevant lineages. A considerable proportion of this transcriptional dysregulation is specifically caused by dosage imbalances in GTF2I, which encodes a key transcription factor at 7q11.23 that is associated with the LSD1 repressive chromatin complex and silences its dosage-sensitive targets.
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Previous work established the largest cohort of 7q11.23 patient-derived iPSC lines and revealed major disease-relevant transcriptional dysregulation apparent at the pluripotent state and exacerbated upon differentiation.
“Our previous work had established the largest cohort of 7q11.23 patient-derived induced pluripotent stem cell (iPSC) lines and revealed major disease-relevant transcriptional dysregulation that was already apparent at the pluripotent state and became further exacerbated upon differentiation (16).”
Ethics approvals for the original iPSC cohort also apply to the additional samples included in this study.
“Ethics approvals were reported in the study that established the original iPSC cohort (16) and also apply to the additional samples included in this study (7dupASD3 and CTL4R).”
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- Authors
- Adamo, A., Atashpaz, S., Germain, P.-L., Zanella, M., D'Agostino, G., Albertin, V., Chenoweth, J., Micale, L., Fusco, C., Unger, C., Augello, B., Palumbo, O., Hamilton, B., Carella, M., Donti, E., Pruneri, G., Selicorni, A., Biamino, E., Prontera, P., McKay, R., Merla, G., & Testa, G.
- Affiliations
- European Institute of Oncology (IT)
- Lieber Institute for Brain Development (US)
- Casa Sollievo della Sofferenza (IT)
- University of Sheffield (GB)
- University of Perugia (IT)
- Azienda Ospedaliera San Gerardo (IT)
- University of Turin (IT)
- University of Milan (IT)
- Corresponding author
- Testa, Giuseppe
- ORCID
- Venue
- Nature Genetics
- Published
- 2014-12-15
- Volume
- 47
- Issue
- 2
- Pages
- 132-141
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2032600544
- Cited by
- 129
- References
- 70
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 19 · 2019: 11 · 2018: 13 · 2017: 14 · 2016: 16 · 2015: 11
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- copy number variation, dosage imbalance, induced pluripotent stem cells, GTF2I, Williams syndrome, transcriptional dysregulation, LSD1, chromatin silencing, neurocognitive phenotype, patient-derived cell models, cell differentiation
- MeSH terms
- Cell Differentiation, Chromosomes, Human, Pair 7, Gene Expression Regulation, Humans, Phenotype, Cohort Studies, Sequence Analysis, RNA, Gene Dosage, Williams Syndrome, Cell Lineage, Transcription Factors, TFII, Oligonucleotide Array Sequence Analysis, Gene Duplication, Gene Expression Profiling, Pluripotent Stem Cells, Comparative Genomic Hybridization, Histone Demethylases, DNA Copy Number Variations
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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