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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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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-74CB-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-433A-3
Genre: Journal Article

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 Creators:
Mutzel, Verena1, Author              
Okamoto, Ikuhiro , Author
Dunkel, Ilona1, Author              
Saitou, Mitinori , Author
Giorgetti, Luca, Author
Heard, Edith , Author
Schulz, Edda G.1, Author              
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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Free keywords: X-chromosome inactivation, gene-regulatory networks, mathematical modelling, feedback loops, systems biology, mono-allelic expression, transcriptional interference, antisense transcription
 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.

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Language(s): eng - English
 Dates: 2017-10-17
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1101/204909
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Title: bioRxive
Source Genre: Journal
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Publ. Info: Cold Spring Harbor, NY : Cold Spring Harbor Laboratory
Pages: - Volume / Issue: 2017 Sequence Number: - Start / End Page: 1 - 54 Identifier: -