Cell Stem Cell
Volume 20, Issue 5, 4 May 2017, Pages 706-719.e7
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Article
DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells

https://doi.org/10.1016/j.stem.2017.03.002Get rights and content
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Highlights

  • Transcriptional and epigenetic patterns were compared between isogenic ESCs and EGCs

  • DNA methylation levels correlate with the X chromosome-to-autosome ratio

  • Male and female blastocysts exhibit similarly low methylation levels

  • DUSP9 overexpression reduces, while Dusp9 loss increases, methylation levels in ESCs

Summary

Blastocyst-derived embryonic stem cells (ESCs) and gonad-derived embryonic germ cells (EGCs) represent two classic types of pluripotent cell lines, yet their molecular equivalence remains incompletely understood. Here, we compare genome-wide methylation patterns between isogenic ESC and EGC lines to define epigenetic similarities and differences. Surprisingly, we find that sex rather than cell type drives methylation patterns in ESCs and EGCs. Cell fusion experiments further reveal that the ratio of X chromosomes to autosomes dictates methylation levels, with female hybrids being hypomethylated and male hybrids being hypermethylated. We show that the X-linked MAPK phosphatase DUSP9 is upregulated in female compared to male ESCs, and its heterozygous loss in female ESCs leads to male-like methylation levels. However, male and female blastocysts are similarly hypomethylated, indicating that sex-specific methylation differences arise in culture. Collectively, our data demonstrate the epigenetic similarity of sex-matched ESCs and EGCs and identify DUSP9 as a regulator of female-specific hypomethylation.

Keywords

embryonic stem cells
embryonic germ cells
inner cell mass
primordial germ cells
pluripotency
DNA methylation
genomic imprinting
X chromosome
Dusp9
cell fusion

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