DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells

Publication date: Available online 30 March 2017
Source:Cell Stem Cell
Author(s): Jiho Choi, Kendell Clement, Aaron J. Huebner, Jamie Webster, Christopher M. Rose, Justin Brumbaugh, Ryan M. Walsh, Soohyun Lee, Andrej Savol, Jean-Pierre Etchegaray, Hongcang Gu, Patrick Boyle, Ulrich Elling, Raul Mostoslavsky, Ruslan Sadreyev, Peter J. Park, Steven P. Gygi, Alexander Meissner, Konrad Hochedlinger
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.

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Teaser

The molecular equivalence of ESCs and EGCs remains incompletely understood. Choi et al. show that ESCs and EGCs are highly similar and that sex rather than cell type drives the transcriptional and epigenetic differences observed between individual cell lines. Female-specific hypomethylation is partially due to upregulation of the X-linked MAPK phosphatase DUSP9.


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