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  Identification of X-chromosomal genes that drive global X-dosage effects in mammals

Genolet, O., Monaco, A. A., Dunkel, I., Boettcher, M., & Schulz, E. G. (2020). Identification of X-chromosomal genes that drive global X-dosage effects in mammals. Unpublished Manuscript.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-6123-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-6124-4
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Genolet_2020.pdf (Preprint), 5MB
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 Creators:
Genolet, Oriana1, Author              
Monaco, Anna A.1, 2, Author              
Dunkel, Ilona1, Author              
Boettcher, Michael 3, 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              
2IRI Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany, ou_persistent22              
3Medical Faculty, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany , ou_persistent22              

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 Abstract: X-chromosomal genes contribute to sex differences, in particular during early development, whenboth X chromosomes are active in females. Here, double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting thedifferentiation-promoting MAP kinase (MAPK) signalling pathway and delaying differentiation. Toidentify the genetic basis of these sex differences, we have performed a series of CRISPR knockoutscreens in murine embryonic stem cells to comprehensively identify X-linked genes that cause thefemale pluripotency phenotype. We found multiple genes that act in concert, among which Klhl13plays a central role. We show that this E3 ubiquitin ligase substrate adaptor protein promotes pluripotency factor expression, delays differentiation and represses MAPK target genes, and weidentify putative substrates. We thus elucidate the mechanisms that drive sex-induced differences inpluripotent cells with implications for gender medicine in the context of induced pluripotent stem cellbased therapies.

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Language(s): eng - English
 Dates: 2020-03-09
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2020.03.09.983544
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Title: bioRxiv (Preprint-Server)
Source Genre: Journal
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Publ. Info: New York : Cold Spring Harbor Laboratory
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