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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • 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

摘要

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.