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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. (2021). Identification of X-chromosomal genes that drive global X-dosage effects in mammals. Genome Biology, 22: 110. doi:10.1186/s13059-021-02321-2.

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Genome Biology_Genolet et al_2021.pdf (Verlagsversion), 3MB
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Genome Biology_Genolet et al_2021.pdf
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© 2021. The Author(s)

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Genolet, Oriana1, Autor           
Monaco, Anna A.1, 2, Autor           
Dunkel, Ilona1, Autor           
Boettcher, Michael 3, 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              
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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Schlagwörter: X chromosome Gene dosage Embryonic stem cells Sex differences Pluripotency MAPK signaling CRISPR screen Dusp9 Klhl13
 Zusammenfassung: Background: X-chromosomal genes contribute to sex differences, in particular
during early development, when both X chromosomes are active in females. Double X-dosage shifts female pluripotent cells towards the naive stem cell state by
increasing pluripotency factor expression, inhibiting the differentiation-promoting
MAP kinase (MAPK) signaling pathway, and delaying differentiation.
Results: To identify the genetic basis of these sex differences, we use a two-step
CRISPR screening approach to comprehensively identify X-linked genes that cause the female pluripotency phenotype in murine embryonic stem cells. A primary chromosome-wide CRISPR knockout screen and three secondary screens assaying for different aspects of the female pluripotency phenotype allow us to uncover multiple genes that act in concert and to disentangle their relative roles. Among them, we identify Dusp9 and Klhl13 as two central players. While Dusp9 mainly affects MAPK pathway intermediates, Klhl13 promotes pluripotency factor expression and delays
differentiation, with both factors jointly repressing MAPK target gene expression.
Conclusions: Here, we elucidate the mechanisms that drive sex-induced differences
in pluripotent cells and our approach serves as a blueprint to discover the genetic basis of the phenotypic consequences of other chromosomal effects.

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Sprache(n): eng - English
 Datum: 2021-03-222021-04-16
 Publikationsstatus: Online veröffentlicht
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 Identifikatoren: DOI: 10.1186/s13059-021-02321-2
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Titel: Genome Biology
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: London : BioMed Central Ltd.
Seiten: - Band / Heft: 22 Artikelnummer: 110 Start- / Endseite: - Identifikator: ISSN: 1474-760X
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000224390_1