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DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells
Jiho Choi1, Kendell Clement2, Aaron J Huebner1
1Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cell Stem Cell
|April 4, 2017
Summary
Sex, not cell type, dictates DNA methylation in embryonic stem cells (ESCs) and embryonic germ cells (EGCs). Female cells are hypomethylated due to DUSP9, a difference that emerges during cell culture.
Area of Science:
- Epigenetics
- Stem Cell Biology
- Genomics
Background:
- Embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are key pluripotent cell types.
- Their molecular similarities and differences, particularly epigenetic profiles, are not fully understood.
Purpose of the Study:
- To compare genome-wide methylation patterns between isogenic ESCs and EGCs.
- To define epigenetic similarities and differences between these cell types.
- To investigate the role of sex in driving these epigenetic patterns.
Main Methods:
- Genome-wide methylation profiling of ESCs and EGCs.
- Cell fusion experiments to assess the impact of X chromosome dosage.
- Gene expression analysis of X-linked genes.
- Gene knockout studies.
Main Results:
- Sex, rather than cell type, was found to be the primary driver of methylation patterns in ESCs and EGCs.
- Cell fusion experiments revealed that the X chromosome to autosome ratio dictates methylation levels, with females being hypomethylated and males hypermethylated.
- The X-linked gene DUSP9 was upregulated in female ESCs, and its loss led to male-like methylation levels.
- Sex-specific methylation differences were observed to arise during cell culture, not in blastocysts.
Conclusions:
- Sex-matched ESCs and EGCs exhibit significant epigenetic similarity.
- DUSP9 is identified as a key regulator of female-specific hypomethylation in ESCs.
- Epigenetic sex differences in these pluripotent cells emerge during in vitro culture.