Cell Reports (Sep 2015)
PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells
- Partha Pratim Das,
- David A. Hendrix,
- Effie Apostolou,
- Alice H. Buchner,
- Matthew C. Canver,
- Semir Beyaz,
- Damir Ljuboja,
- Rachael Kuintzle,
- Woojin Kim,
- Rahul Karnik,
- Zhen Shao,
- Huafeng Xie,
- Jian Xu,
- Alejandro De Los Angeles,
- Yingying Zhang,
- Junho Choe,
- Don Leong Jia Jun,
- Xiaohua Shen,
- Richard I. Gregory,
- George Q. Daley,
- Alexander Meissner,
- Manolis Kellis,
- Konrad Hochedlinger,
- Jonghwan Kim,
- Stuart H. Orkin
Affiliations
- Partha Pratim Das
- 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
- David A. Hendrix
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA
- Effie Apostolou
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA
- Alice H. Buchner
- 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
- Matthew C. Canver
- 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
- Semir Beyaz
- 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
- Damir Ljuboja
- 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
- Rachael Kuintzle
- 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
- Woojin Kim
- 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
- Rahul Karnik
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA
- Zhen Shao
- 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
- Huafeng Xie
- 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
- Jian Xu
- 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
- Alejandro De Los Angeles
- 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
- Yingying Zhang
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA
- Junho Choe
- 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
- Don Leong Jia Jun
- 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
- Xiaohua Shen
- 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
- Richard I. Gregory
- 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
- George Q. Daley
- 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
- Alexander Meissner
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA
- Manolis Kellis
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA
- Konrad Hochedlinger
- Howard Hughes Medical Institute (HHMI), Boston, MA 02115, USA
- Jonghwan Kim
- 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
- Stuart H. Orkin
- 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
- DOI
- https://doi.org/10.1016/j.celrep.2015.07.053
- Journal volume & issue
-
Vol. 12,
no. 9
pp. 1456 – 1470
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.
