G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2016 Apr 8

PMID 27052169

Citations 36

Authors

Tuo Zhang

Ausma Termanis

Burak Ozkan

Xun X Bao

Jayne Culley

Flavia de Lima Alves

Juri Rappsilber

Bernard Ramsahoye

Irina Stancheva

Affiliations

Soon will be listed here.

Abstract

DNA methylation at imprinting control regions (ICRs) is established in gametes in a sex-specific manner and has to be stably maintained during development and in somatic cells to ensure the correct monoallelic expression of imprinted genes. In addition to DNA methylation, the ICRs are marked by allele-specific histone modifications. Whether these marks are essential for maintenance of genomic imprinting is largely unclear. Here, we show that the histone H3 lysine 9 methylases G9a and GLP are required for stable maintenance of imprinted DNA methylation in embryonic stem cells; however, their catalytic activity and the G9a/GLP-dependent H3K9me2 mark are completely dispensable for imprinting maintenance despite the genome-wide loss of non-imprinted DNA methylation in H3K9me2-depleted cells. We provide additional evidence that the G9a/GLP complex protects imprinted DNA methylation by recruitment of de novo DNA methyltransferases, which antagonize TET dioxygenass-dependent erosion of DNA methylation at ICRs.

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References

Peters J . The role of genomic imprinting in biology and disease: an expanding view. Nat Rev Genet. 2014; 15(8):517-30. DOI: 10.1038/nrg3766. View

Liu Y, Toh H, Sasaki H, Zhang X, Cheng X . An atomic model of Zfp57 recognition of CpG methylation within a specific DNA sequence. Genes Dev. 2012; 26(21):2374-9. PMC: 3489995. DOI: 10.1101/gad.202200.112. View

Shipony Z, Mukamel Z, Mendelson Cohen N, Landan G, Chomsky E, Zeliger S . Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells. Nature. 2014; 513(7516):115-9. DOI: 10.1038/nature13458. View

Barlow D, Bartolomei M . Genomic imprinting in mammals. Cold Spring Harb Perspect Biol. 2014; 6(2). PMC: 3941233. DOI: 10.1101/cshperspect.a018382. View

Piccolo F, Fisher A . Getting rid of DNA methylation. Trends Cell Biol. 2013; 24(2):136-43. DOI: 10.1016/j.tcb.2013.09.001. View

Quenneville S, Verde G, Corsinotti A, Kapopoulou A, Jakobsson J, Offner S . In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell. 2011; 44(3):361-72. PMC: 3210328. DOI: 10.1016/j.molcel.2011.08.032. View

Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H . PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol. 2006; 9(1):64-71. DOI: 10.1038/ncb1519. View

Ferguson-Smith A . Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet. 2011; 12(8):565-75. DOI: 10.1038/nrg3032. View

Skourti-Stathaki K, Kamieniarz-Gdula K, Proudfoot N . R-loops induce repressive chromatin marks over mammalian gene terminators. Nature. 2014; 516(7531):436-9. PMC: 4272244. DOI: 10.1038/nature13787. View

10.

Lienert F, Mohn F, Tiwari V, Baubec T, Roloff T, Gaidatzis D . Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells. PLoS Genet. 2011; 7(6):e1002090. PMC: 3107198. DOI: 10.1371/journal.pgen.1002090. View

11.

Nakamura T, Liu Y, Nakashima H, Umehara H, Inoue K, Matoba S . PGC7 binds histone H3K9me2 to protect against conversion of 5mC to 5hmC in early embryos. Nature. 2012; 486(7403):415-9. DOI: 10.1038/nature11093. View

12.

Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M . G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 2002; 16(14):1779-91. PMC: 186403. DOI: 10.1101/gad.989402. View

13.

Smallwood S, Lee H, Angermueller C, Krueger F, Saadeh H, Peat J . Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods. 2014; 11(8):817-820. PMC: 4117646. DOI: 10.1038/nmeth.3035. View

14.

Henckel A, Nakabayashi K, Sanz L, Feil R, Hata K, Arnaud P . Histone methylation is mechanistically linked to DNA methylation at imprinting control regions in mammals. Hum Mol Genet. 2009; 18(18):3375-83. DOI: 10.1093/hmg/ddp277. View

15.

Shinkai Y, Tachibana M . H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev. 2011; 25(8):781-8. PMC: 3078703. DOI: 10.1101/gad.2027411. View

16.

Smith Z, Meissner A . DNA methylation: roles in mammalian development. Nat Rev Genet. 2013; 14(3):204-20. DOI: 10.1038/nrg3354. View

17.

Xin Z, Tachibana M, Guggiari M, Heard E, Shinkai Y, Wagstaff J . Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center. J Biol Chem. 2003; 278(17):14996-5000. DOI: 10.1074/jbc.M211753200. View

18.

Hirasawa R, Chiba H, Kaneda M, Tajima S, Li E, Jaenisch R . Maternal and zygotic Dnmt1 are necessary and sufficient for the maintenance of DNA methylation imprints during preimplantation development. Genes Dev. 2008; 22(12):1607-16. PMC: 2428059. DOI: 10.1101/gad.1667008. View

19.

Myant K, Termanis A, Sundaram A, Boe T, Li C, Merusi C . LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. Genome Res. 2010; 21(1):83-94. PMC: 3012929. DOI: 10.1101/gr.108498.110. View

20.

Smith Z, Chan M, Mikkelsen T, Gu H, Gnirke A, Regev A . A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012; 484(7394):339-44. PMC: 3331945. DOI: 10.1038/nature10960. View