Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids
While random X-chromosome inactivation in female cells of placental mammals silences one allele of the majority of X-chromosomal genes, a considerable fraction is only incompletely and variably inactivated. Human model systems to study the dynamics of incomplete X-inactivation are limited mostly to postmortem tissue, thereby disregarding developmental trajectories. Here, we used clonal human female induced pluripotent stem cells to track allele-specific expression of X-chromosomal genes along neural differentiation. We discovered dynamic reactivation and late-silencing of gene expression from the inactive X-chromosome leading to differentiation-induced locus- and lineage-specific usage of the two X-chromosomal alleles. In brain organoids modeling Opitz BBB/G syndrome, an X-linked neurodevelopmental disorder, reactivation of alleles from the inactive X-chromosome rescued cellular phenotypes and led to intermediate manifestations in female tissue. Taken together, our data demonstrate that alleles on the inactive X-chromosome can serve as a critical reservoir dynamically used during differentiation, thereby enhancing resilience of female neural tissue.
Authors
- Elisa Gabassi (ORCID: https://orcid.org/0000-0001-6053-503X)
- Elisa Cesare (ORCID: https://orcid.org/0000-0002-7171-8357)
- Stephan Käseberg (ORCID: https://orcid.org/0000-0002-7882-5745)
- Marco Bertin
- Nicola Elvassore (ORCID: https://orcid.org/0000-0002-7029-6287)
- Nadine Bobon
- Peter Baumann (ORCID: https://orcid.org/0000-0003-4892-1485)
- Hristo Todorov (ORCID: https://orcid.org/0000-0003-2734-7701)
- Federica Furlanetto (ORCID: https://orcid.org/0000-0003-0963-3560)
- Ramkumar Menon (ORCID: https://orcid.org/0000-0001-9213-6105)
- Katja Luck (ORCID: https://orcid.org/0000-0003-2336-9225)
- Benjamin Lohrer (ORCID: https://orcid.org/0000-0002-8042-342X)
- Heiko Brennenstuhl (ORCID: https://orcid.org/0000-0002-6909-0003)
- Marisa Karow (ORCID: https://orcid.org/0000-0003-4935-1365)
- Sarah Frank (ORCID: https://orcid.org/0000-0002-3339-8495)
- Jennifer Krummeich
- Azza Soliman
- S. Schweiger
- H. M. B. Ibrahim
- J. Winter
- P. Lunt
- B. Winner
- S. Falk
- A. Mas-Sanchez
- V. Engelhardt
- C. Foerster
- S. Gerber
- S. Diederich
- J. Winkler
- MF Basilicata
- B. Berninger
- E. Weis
- L. Birschmann
Institutions
- University of Padua (IT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- King's College London (GB)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- The Francis Crick Institute (GB)
- University Hospital Heidelberg (DE)
- University of Bristol (GB)
- Universitätsklinikum Erlangen (DE)
- Leibniz Institute for Resilience Research (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Quantitative BioSciences (US)
- Institut für Psychogerontologie (DE)
- Institute of Molecular Biology (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-14
- DOI
- https://doi.org/10.1038/s41467-026-68428-x
- Citations
- 2
- Primary Topic
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 61.86
Funders
- Wellcome Trust
- Francis Crick Institute
- Cancer Research UK
- Deutsche Forschungsgemeinschaft
- Ludwig-Maximilians-Universität München
- Medical Research Council