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 & 5 others Alexander Meissner, Manolis Kellis, Konrad Hochedlinger, Jonghwan Kim, Stuart H. Orkin

Research output: Contribution to journalArticle

25 Citations (Scopus)

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. Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are both typically correlated with gene repression. Das et al. find that PRC2 prevents recruitment of Dnmt3s and DNAme at the IG-DMR element, thus allowing proper expression of the nearby maternal Gtl2-Rian-Mirg locus.

Original languageEnglish (US)
Article number1953
Pages (from-to)1456-1470
Number of pages15
JournalCell Reports
Volume12
Issue number9
DOIs
StatePublished - Sep 1 2015

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Polycomb Repressive Complex 2
DNA Methylation
Stem cells
Mothers
Methyltransferases
Genes
Long Noncoding RNA
Mouse Embryonic Stem Cells
MicroRNAs

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Das, P. P., Hendrix, D. A., Apostolou, E., Buchner, A. H., Canver, M. C., Beyaz, S., ... Orkin, S. H. (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. Cell Reports, 12(9), 1456-1470. [1953]. https://doi.org/10.1016/j.celrep.2015.07.053

PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells. / Das, Partha Pratim; Hendrix, David A.; Apostolou, Effie; Buchner, Alice H.; Canver, Matthew C.; Beyaz, Semir; Ljuboja, Damir; Kuintzle, Rachael; Kim, Woojin; Karnik, Rahul; Shao, Zhen; Xie, Huafeng; Xu, Jian; De Los Angeles, Alejandro; Zhang, Yingying; Choe, Junho; Jun, Don Leong Jia; Shen, Xiaohua; Gregory, Richard I.; Daley, George Q.; Meissner, Alexander; Kellis, Manolis; Hochedlinger, Konrad; Kim, Jonghwan; Orkin, Stuart H.

In: Cell Reports, Vol. 12, No. 9, 1953, 01.09.2015, p. 1456-1470.

Research output: Contribution to journalArticle

Das, PP, Hendrix, DA, Apostolou, E, Buchner, AH, Canver, MC, Beyaz, S, Ljuboja, D, Kuintzle, R, Kim, W, Karnik, R, Shao, Z, Xie, H, Xu, J, De Los Angeles, A, Zhang, Y, Choe, J, Jun, DLJ, Shen, X, Gregory, RI, Daley, GQ, Meissner, A, Kellis, M, Hochedlinger, K, Kim, J & Orkin, SH 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', Cell Reports, vol. 12, no. 9, 1953, pp. 1456-1470. https://doi.org/10.1016/j.celrep.2015.07.053
Das, Partha Pratim ; Hendrix, David A. ; Apostolou, Effie ; Buchner, Alice H. ; Canver, Matthew C. ; Beyaz, Semir ; Ljuboja, Damir ; Kuintzle, Rachael ; Kim, Woojin ; Karnik, Rahul ; Shao, Zhen ; Xie, Huafeng ; Xu, Jian ; De Los Angeles, Alejandro ; Zhang, Yingying ; Choe, Junho ; Jun, Don Leong Jia ; Shen, Xiaohua ; Gregory, Richard I. ; Daley, George Q. ; Meissner, Alexander ; Kellis, Manolis ; Hochedlinger, Konrad ; Kim, Jonghwan ; Orkin, Stuart H. / PRC2 Is Required to Maintain Expression of the Maternal Gtl2-Rian-Mirg Locus by Preventing De Novo DNA Methylation in Mouse Embryonic Stem Cells. In: Cell Reports. 2015 ; Vol. 12, No. 9. pp. 1456-1470.
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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. Polycomb Repressive Complex 2 (PRC2) function and DNA methylation (DNAme) are both typically correlated with gene repression. Das et al. find that PRC2 prevents recruitment of Dnmt3s and DNAme at the IG-DMR element, thus allowing proper expression of the nearby maternal Gtl2-Rian-Mirg locus.",
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AU - Das, Partha Pratim

AU - Hendrix, David A.

AU - Apostolou, Effie

AU - Buchner, Alice H.

AU - Canver, Matthew C.

AU - Beyaz, Semir

AU - Ljuboja, Damir

AU - Kuintzle, Rachael

AU - Kim, Woojin

AU - Karnik, Rahul

AU - Shao, Zhen

AU - Xie, Huafeng

AU - Xu, Jian

AU - De Los Angeles, Alejandro

AU - Zhang, Yingying

AU - Choe, Junho

AU - Jun, Don Leong Jia

AU - Shen, Xiaohua

AU - Gregory, Richard I.

AU - Daley, George Q.

AU - Meissner, Alexander

AU - Kellis, Manolis

AU - Hochedlinger, Konrad

AU - Kim, Jonghwan

AU - Orkin, Stuart H.

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