Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids
- M. Bertin
- H. Todorov
- S. Frank
- S. Käseberg
- R. Menon
- E. Gabassi
- C. Foerster
- N. Bobon
- F. Furlanetto
- A. Soliman
- H. M. B. Ibrahim
- V. Engelhardt
- L. Birschmann
- H. Brennenstuhl
- B. Lohrer
- A. Mas-Sanchez
- E. Cesare
- J. Winter
- J. Krummeich
- J. Winkler
- B. Winner
- E. Weis
- S. Diederich
- K. Luck
- P. Lunt
- S. Gerber
- P. Baumann
- N. Elvassore
- B. Berninger
- MF Basilicata
- S. Schweiger
- S. Falk
- M. Karow
2026-01-14
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.