Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids
Abstract
Abstract 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.
Article Details
Authors (33)
M. Bertin
Sorbonne Université, CNSR, MONARIS, UMR8233 2 , F-75005 Paris,
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