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Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation

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Mutzel,  Verena
Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Dunkel,  Ilona
Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Schulz,  Edda G.
Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Mutzel, V., Okamoto, I., Dunkel, I., Saitou, M., Giorgetti, L., Heard, E., et al. (2017). Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation. bioRxive, 2017, 1-54. doi:10.1101/204909.


Cite as: http://hdl.handle.net/21.11116/0000-0000-74CB-9
Abstract
In female mammal s, dosage compensation for X-linked genes is ensured through random X-chromosome inactivation, which is initiated by mono-allelic up-regulation of Xist . We use mathematical modeling to identify the regulatory principles required to establish the mono-allelic and female-specific Xist expression pattern and test model predictions experimentally. A cis -acting positive feedback, which in mice is mediated by mutual repression of Xist and its antisense transcript Tsix , together with a trans -acting negative feedba ck are sufficient to explain mono-allelic Xist up-regulation. The model can reproduce data from several mutant, aneuploid and polyploid murine cell lines and explain s Xist expression patterns in other mammalian species. Furthermore, it predicts that transient , reversible bi-allelic Xist expression is not restricted to rabbits and humans but can also occur in mice, which we indeed confirm to occur in mouse embryos. Overall, our study provides a conceptual framework of the molecular mechanisms required to initiate random X-chromosome inactivation.