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Cell Rep. 2015 Sep 1;12(9):1456-70. doi: 10.1016/j.celrep.2015.07.053. Epub 2015 Aug 20.

PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells.

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute (HHMI), Boston, MA 02115, USA.
2
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Department of Biochemistry and Biophysics, School of Electrical Engineering and Computer Science, Oregon State University, 2011 Ag and Life Science Building, Corvallis, OR 97331-7305, USA.
3
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA; Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA.
4
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Molecular Biology Program, International Max Planck Research School, Georg-August-Universität Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
5
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Biochemistry and Biophysics, School of Electrical Engineering and Computer Science, Oregon State University, 2011 Ag and Life Science Building, Corvallis, OR 97331-7305, USA.
7
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA.
8
Stem Cell Program, Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
9
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; School of Chemical and Life Sciences, Singapore Polytechnic, 500 Dover Road, Singapore 139651, Singapore.
10
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
11
Howard Hughes Medical Institute (HHMI), Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA; Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA.
12
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute (DFCI), Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute (HHMI), Boston, MA 02115, USA. Electronic address: stuart_orkin@dfci.harvard.edu.

Abstract

Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are typically correlated with gene repression. Here, we show that PRC2 is required to maintain expression of maternal microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) from the Gtl2-Rian-Mirg locus, which is essential for full pluripotency of iPSCs. In the absence of PRC2, the entire locus becomes transcriptionally repressed due to gain of DNAme at the intergenic differentially methylated regions (IG-DMRs). Furthermore, we demonstrate that the IG-DMR serves as an enhancer of the maternal Gtl2-Rian-Mirg locus. Further analysis reveals that PRC2 interacts physically with Dnmt3 methyltransferases and reduces recruitment to and subsequent DNAme at the IG-DMR, thereby allowing for proper expression of the maternal Gtl2-Rian-Mirg locus. Our observations are consistent with a mechanism through which PRC2 counteracts the action of Dnmt3 methyltransferases at an imprinted locus required for full pluripotency.

PMID:
26299972
PMCID:
PMC5384103
DOI:
10.1016/j.celrep.2015.07.053
[Indexed for MEDLINE]
Free PMC Article

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