Cdk8 and Hira mutations trigger X chromosome elimination in naive female hybrid mouse embryonic stem cells.
Cdk8
Hira
Mouse embryonic stem cells
Mus musculus castaneus
Naive pluripotency
X chromosome elimination
Journal
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology
ISSN: 1573-6849
Titre abrégé: Chromosome Res
Pays: Netherlands
ID NLM: 9313452
Informations de publication
Date de publication:
10 Oct 2024
10 Oct 2024
Historique:
received:
12
04
2024
accepted:
18
09
2024
revised:
11
09
2024
medline:
11
10
2024
pubmed:
11
10
2024
entrez:
10
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39390295
doi: 10.1007/s10577-024-09756-w
pii: 10.1007/s10577-024-09756-w
doi:
Substances chimiques
Cyclin-Dependent Kinase 8
EC 2.7.11.22
Cell Cycle Proteins
0
Cdk8 protein, mouse
EC 2.7.11.22
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
12Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 31003A_175643/1
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 31003A_175643/1
Informations de copyright
© 2024. The Author(s).
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