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

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.

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Mutzel.pdf (Preprint), 3MB
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 Urheber:
Mutzel, Verena1, Autor           
Okamoto, Ikuhiro , Autor
Dunkel, Ilona1, Autor           
Saitou, Mitinori , Autor
Giorgetti, Luca, Autor
Heard, Edith , Autor
Schulz, Edda G.1, Autor           
Affiliations:
1Regulatory Networks in Stem Cells (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117286              

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Schlagwörter: X-chromosome inactivation, gene-regulatory networks, mathematical modelling, feedback loops, systems biology, mono-allelic expression, transcriptional interference, antisense transcription
 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2017-10-17
 Publikationsstatus: Online veröffentlicht
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 Ort, Verlag, Ausgabe: -
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 Identifikatoren: DOI: 10.1101/204909
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Titel: bioRxive
Genre der Quelle: Zeitschrift
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Affiliations:
Ort, Verlag, Ausgabe: Cold Spring Harbor, NY : Cold Spring Harbor Laboratory
Seiten: - Band / Heft: 2017 Artikelnummer: - Start- / Endseite: 1 - 54 Identifikator: -