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  Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

Pacini, G., Dunkel, I., Mages, N., Mutzel, V., Timmermann, B., Marsico, A., et al. (2020). Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution. bioRxiv (The Preprintserver for biology), 2020. doi:10.1101/2020.07.20.211573.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-B8FA-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-B8FB-F
Genre: Journal Article

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 Creators:
Pacini, Guido1, Author              
Dunkel, Ilona1, Author              
Mages, Norbert2, Author              
Mutzel, Verena1, Author              
Timmermann, Bernd2, Author              
Marsico, Annalisa3, 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              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
3Institute for Computational Biology, Helmholtz Center, München, Germany, ou_persistent22              

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 Abstract: To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediateschromosome-wide gene silencing. Cell differentiation, Xist upregulation and silencing are thought tobe coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cellRNA-sequencing. Specifically, we assess the onset of random XCI with high temporal resolution indifferentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploitingthe inter-cellular heterogeneity of XCI onset, we identify Nanog downregulation as its main trigger and discover additional putative Xist regulators. Moreover, we confirm several predictions of thestochastic model of XCI where monoallelic silencing is thought to be ensured through negativefeedback regulation. Finally, we show that genetic variation modulates the XCI process at multiplelevels, providing a potential explanation for the long-known Xce effect, which leads to preferentialinactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of thedifferent levels of regulation that govern the initiation of XCI. The experimental and computationalstrategies we have developed here will allow us to profile random XCI in more physiological contexts,including primary human cells in vivo.

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Language(s): eng - English
 Dates: 2020-07-21
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2020.07.20.211573
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Title: bioRxiv (The Preprintserver for biology)
Source Genre: Journal
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Pages: - Volume / Issue: 2020 Sequence Number: - Start / End Page: - Identifier: -