Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids

Frank S, Todorov H, Menon R, Gabassi E, Furlanetto F, Bobon N, Soliman A, Birschmann L, Engelhardt V, Lohrer B, Brennenstuhl H, Mas-Sanchez A, Cesare E, Winter J, Krummeich J, Winkler J, Winner B, Weis E, Diederich S, Luck K, Lunt P, Gerber S, Baumann P, Elvassore N, Berninger B, Falk S, Karow M (2026)

Publication Language: English

Publication Type: Journal article

Publication year: 2026

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 17

Article Number: 599

Journal Issue: 1

DOI: 10.1038/s41467-026-68428-x

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.

Authors with CRIS profile

Sarah Frank Institut für Biochemie Elisa Gabassi Professur für Biochemie und Molekulare Neurowissenschaften Federica Furlanetto Institut für Biochemie Benjamin Lohrer Professur für Biochemie und Molekulare Neurowissenschaften Jürgen Winkler Professur für Molekulare Neurologie Beate Winner Medizinische Fakultät Sven Falk Lehrstuhl für Biochemie und Pathobiochemie Marisa Karow-Falk Professur für Biochemie und Molekulare Neurowissenschaften

Additional Organisation(s)

Stammzellbiologische Abteilung am Humangenetischen Institut Professur für Stammzell-Modelle seltener neuraler Erkrankungen

Involved external institutions

Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) University of Padua / Universita degli Studi di Padova IT Italy (IT) Institut für Molekulare Biologie gGmbH / Institute of Molecular Biology (IMB) DE Germany (DE)

How to cite

APA:

Frank, S., Todorov, H., Menon, R., Gabassi, E., Furlanetto, F., Bobon, N.,... Karow, M. (2026). Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-68428-x

MLA:

Frank, Sarah, et al. "Dynamic allele usage of X-linked genes ameliorates neurodevelopmental disease phenotypes in brain organoids." Nature Communications 17.1 (2026).

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