Cdk8 and Hira mutations trigger X chromosome elimination in naive female hybrid mouse embryonic stem cells
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2024-10-10
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Journal Article
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yes
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Abstract
Mouse embryonic stem cells (ESCs) possess a pluripotent developmental potential and a stable karyotype. An exception is the frequent loss of one X chromosome in female ESCs derived from inbred mice. In contrast, female ESCs from crosses between different Mus musculus subspecies often maintain two X chromosomes and can model X chromosome inactivation. Here we report that combined mutations of Hira and Cdk8 induce rapid loss of one X chromosome in a Mus musculus castaneus hybrid female ESC line that originally maintains two X chromosomes. We show that MEK1 inhibition, which is used for culturing naive pluripotent ESCs is sufficient to induce X chromosome loss. In conventional ESC media, Hira and Cdk8 mutant ESCs maintain both X chromosomes. Induction of X chromosome loss by switching to naive culture media allows us to perform kinetic measurements for calculating the chromosome loss rate. Our analysis shows that X chromosome loss is not explained by selection of XO cells, but likely driven by a process of chromosome elimination. We show that elimination of the X chromosome occurs with a rate of 0.3% per cell per division, which exceeds reported autosomal loss rates by 3 orders of magnitude. We show that chromosomes 8 and 11 are stably maintained. Notably, Xist expression from one of the two X chromosomes rescues X chromosomal instability in ΔHiraΔCdk8 ESCs. Our study defines mutations of Hira and Cdk8 as molecular drivers for X chromosome elimination in naive female ESCs and describes a cell system for elucidating the underlying mechanism.
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published
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Journal / series
Volume
32 (4)
Pages / Article No.
12
Publisher
Springer
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Subject
Hira; Cdk8; X chromosome elimination; Mouse embryonic stem cells; naive pluripotency; Mus musculus castaneus; Animals; Female; Mice; X Chromosome; Cyclin-Dependent Kinase 8; Mouse Embryonic Stem Cells; X Chromosome Inactivation; Mutation; Cell Cycle Proteins; Transcription factors
Organisational unit
03978 - Wutz, Anton / Wutz, Anton
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Funding
152814 - X chromosome reactivation in development and transformation (SNF)