title: PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells.
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.
authors: 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.
authors: Partha Pratim
authors: PP
authors: Das
authors: 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.
authors: David A
authors: DA
authors: Hendrix
authors: 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.
authors: Effie
authors: E
authors: Apostolou
authors: 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.
authors: Alice H
authors: AH
authors: Buchner
authors: 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.
authors: Matthew C
authors: MC
authors: Canver
authors: 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.
authors: Semir
authors: S
authors: Beyaz
authors: 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.
authors: Damir
authors: D
authors: Ljuboja
authors: 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.
authors: Rachael
authors: R
authors: Kuintzle
authors: 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.
authors: Woojin
authors: W
authors: Kim
authors: 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.
authors: Rahul
authors: R
authors: Karnik
authors: 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.
authors: Zhen
authors: Z
authors: Shao
authors: 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.
authors: Huafeng
authors: H
authors: Xie
authors: 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.
authors: Jian
authors: J
authors: Xu
authors: 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.
authors: Alejandro
authors: A
authors: De Los Angeles
authors: 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.
authors: Yingying
authors: Y
authors: Zhang
authors: 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.
authors: Junho
authors: J
authors: Choe
authors: 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.
authors: Don Leong Jia
authors: DL
authors: Jun
authors: 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.
authors: Xiaohua
authors: X
authors: Shen
authors: 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.
authors: Richard I
authors: RI
authors: Gregory
authors: 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.
authors: George Q
authors: GQ
authors: Daley
authors: 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.
authors: Alexander
authors: A
authors: Meissner
authors: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
authors: Manolis
authors: M
authors: Kellis
authors: 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.
authors: Konrad
authors: K
authors: Hochedlinger
authors: 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.
authors: Jonghwan
authors: J
authors: Kim
authors: 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.
authors: Stuart H
authors: SH
authors: Orkin
mesh_terms: D000818:Animals; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018392:Genomic Imprinting; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: C422882:MEG3 non-coding RNA, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; C441460:Rian protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D063151:Polycomb Repressive Complex 2