한빛사 논문
Massachusetts General Hospital, Harvard Stem Cell Institute, Harvard University
Abstract
Jiho Choi,1,2,3,8 Kendell Clement,2,3,4,8 Aaron J. Huebner,1,2,3 Jamie Webster,2,3,4 Christopher M. Rose,5 Justin Brumbaugh,1,2,3 Ryan M. Walsh,1,2,3 Soohyun Lee,6 Andrej Savol,1 Jean-Pierre Etchegaray,1 Hongcang Gu,4 Patrick Boyle,4 Ulrich Elling,7 Raul Mostoslavsky,1 Ruslan Sadreyev,1 Peter J. Park,6 Steven P. Gygi,5 Alexander Meissner,2,3,4,* and Konrad Hochedlinger1,2,3,9,*
1Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
2Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA
3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
6Department of Biomedical Informatics, Harvard Medical School, 10 Shattuck Street, Boston, MA 02115, USA
7Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), 1030 Vienna, Austria
8Co-first author
9Lead Contact
*Correspondence: Alexander Meissner, Konrad Hochedlinger
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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