2014
DOI: 10.1016/j.stem.2013.11.022
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The Two Active X Chromosomes in Female ESCs Block Exit from the Pluripotent State by Modulating the ESC Signaling Network

Abstract: During early development of female mouse embryos, both X chromosomes are transiently active. X gene dosage is then equalized between the sexes through the process of X chromosome inactivation (XCI). Whether the double dose of X-linked genes in females compared with males leads to sex-specific developmental differences has remained unclear. Using embryonic stem cells with distinct sex chromosome compositions as a model system, we show that two X chromosomes stabilize the naive pluripotent state by inhibiting MA… Show more

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Cited by 162 publications
(312 citation statements)
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“…Since these signalling pathways are known to control pluripotency factor expression, the observed changes in signalling activity could account for down-stream effects on the pluripotency network. Interestingly target genes of Mek/Erk signalling are clearly reduced in mESCs with two X-chromosomes, but Mek/Erk phosphorylation levels exhibit the opposite trend [8,36]. This suggests that X-chromosome dosage inhibits MAPK signalling downstream of Erk, leading to reduced target gene expression, but increased Mek and Erk phosphorylation due to negative feedback regulation.…”
Section: Sex Differences In Murine Embryonic Stem Cellsmentioning
confidence: 98%
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“…Since these signalling pathways are known to control pluripotency factor expression, the observed changes in signalling activity could account for down-stream effects on the pluripotency network. Interestingly target genes of Mek/Erk signalling are clearly reduced in mESCs with two X-chromosomes, but Mek/Erk phosphorylation levels exhibit the opposite trend [8,36]. This suggests that X-chromosome dosage inhibits MAPK signalling downstream of Erk, leading to reduced target gene expression, but increased Mek and Erk phosphorylation due to negative feedback regulation.…”
Section: Sex Differences In Murine Embryonic Stem Cellsmentioning
confidence: 98%
“…In population measurements, female XX ESCs therefore express higher levels of those pluripotency factors that are downregulated during the early reversible differentiation step, such as Nanog and Esrrb. Moreover, the signal transduction network adopts a distinct state in female ESCs with increased activity of the pluripotency associated Pi3 K/Akt pathway, and reduced output from the differentiation promoting Mek/Erk and Gsk3/b-Catenin pathways [8,36]. Since these signalling pathways are known to control pluripotency factor expression, the observed changes in signalling activity could account for down-stream effects on the pluripotency network.…”
Section: Sex Differences In Murine Embryonic Stem Cellsmentioning
confidence: 99%
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“…76 This property is attributable to XaXa, since XO cells and XY cells exhibit similarly higher levels of DNA methylation. 76,77 Mechanistically, the expression levels of Dnmt3a and Dnmt3b, but not Dnmt1, are markedly lower in XX cells than in XO and XY cells, 76,77 suggesting that lower activity of de novo methyltransferases due to XaXa is responsible for the global hypomethylation. Indeed, ectopic expression of Dnmt3a or Dnm3b can rescue the reduced methylation levels at particular regions in female ES cells.…”
Section: Epigenetic and Genetic Instability In Female Mouse Es Cellsmentioning
confidence: 99%