title: Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation, rapid target gene repression, and mouse viability.
abstract: GLP and G9a are major H3K9 dimethylases and are essential for mouse early embryonic development. GLP and G9a both harbor ankyrin repeat domains that are capable of binding H3K9 methylation. However, the functional significance of their recognition of H3K9 methylation is unknown. Here, we report that the histone methyltransferase activities of GLP and G9a are stimulated by neighboring nucleosomes that are premethylated at H3K9. These stimulation events function in cis and are dependent on the H3K9 methylation binding activities of ankyrin repeat domains of GLP and G9a. Disruption of the H3K9 methylation-binding activity of GLP in mice causes growth retardation of embryos, ossification defects of calvaria, and postnatal lethality due to starvation of the pups. In mouse embryonic stem cells (ESCs) harboring a mutant GLP that lacks H3K9me1-binding activity, critical pluripotent genes, including Oct4 and Nanog, display inefficient establishment of H3K9me2 and delayed gene silencing during differentiation. Collectively, our study reveals a new activation mechanism for GLP and G9a that plays an important role in ESC differentiation and mouse viability.
authors: College of Life Sciences, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Nan
authors: N
authors: Liu
authors: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Zhuqiang
authors: Z
authors: Zhang
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin Province 130012, China; zhubing@ibp.ac.cn topwuhui@jlu.edu.cn.
authors: Hui
authors: H
authors: Wu
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Yonghua
authors: Y
authors: Jiang
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Lingjun
authors: L
authors: Meng
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Jun
authors: J
authors: Xiong
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Zuodong
authors: Z
authors: Zhao
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Xiaohua
authors: X
authors: Zhou
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Jia
authors: J
authors: Li
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Hong
authors: H
authors: Li
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Yong
authors: Y
authors: Zheng
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: She
authors: S
authors: Chen
authors: National Institute of Biological Sciences, Beijing 102206, China;
authors: Tao
authors: T
authors: Cai
authors: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors: Shaorong
authors: S
authors: Gao
authors: National Institute of Biological Sciences, Beijing 102206, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; zhubing@ibp.ac.cn topwuhui@jlu.edu.cn.
authors: Bing
authors: B
authors: Zhu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019465:Craniofacial Abnormalities / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000071317:Nanog Homeobox Protein; D009707:Nucleosomes / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D011485:Protein Binding
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009707:Nucleosomes; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; C533711:G9a protein, mouse; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: G9a; GLP; H3K9 methylation; cell differentiation; gene repression
references: Mol Cell. 2007 Aug 17;27(4):585-95
references: 17707230
references: Cell. 2007 Mar 9;128(5):1003-12
references: 17350582
references: EMBO Rep. 2011 Mar;12(3):244-51
references: 21331095
references: Curr Opin Cell Biol. 2009 Jun;21(3):359-66
references: 19477626
references: Exp Physiol. 2000 Nov;85(6):645-51
references: 11187960
references: Science. 2012 Aug 24;337(6097):971-5
references: 22923582
references: Nat Chem Biol. 2008 Jun;4(6):344-6
references: 18438403
references: Nat Struct Mol Biol. 2008 Mar;15(3):221-2
references: 18319736
references: J Biol Chem. 2006 Mar 31;281(13):8476-85
references: 16461774
references: Nat Genet. 2009 Feb;41(2):246-50
references: 19151716
references: Curr Biol. 2002 Feb 5;12(3):247-51
references: 11839280
references: Nat Cell Biol. 2006 Feb;8(2):188-94
references: 16415856
references: PLoS Genet. 2011 Jun;7(6):e1002090
references: 21655081
references: Genes Dev. 2002 Jul 15;16(14):1779-91
references: 12130538
references: Nature. 2009 Oct 8;461(7265):762-7
references: 19767730
references: Cell Res. 2009 Oct;19(10):1217-20
references: 19770845
references: Cell. 2011 May 13;145(4):555-70
references: 21529909
references: Genes Dev. 2011 Apr 15;25(8):781-8
references: 21498567
references: Dev Biol. 2014 Feb 15;386(2):395-407
references: 24362066
references: Biol Neonate. 2000 Nov;78(4):293-9
references: 11093009
references: Mol Cell. 2007 Aug 17;27(4):596-608
references: 17707231
references: Philos Trans R Soc Lond B Biol Sci. 2013 Jan 5;368(1609):20110332
references: 23166395
references: Cell. 2012 Sep 28;151(1):181-93
references: 23021224
references: Histochem Cell Biol. 2015 Mar;143(3):259-66
references: 25294562
references: Mol Cell. 2013 Jul 11;51(1):80-91
references: 23849629
references: Cell Res. 2011 Feb;21(2):365-7
references: 21079650
references: Mol Cell. 2007 Oct 12;28(1):1-13
references: 17936700
references: Nat Struct Mol Biol. 2008 Mar;15(3):245-50
references: 18264113
references: Physiol Rev. 2009 Jan;89(1):1-26
references: 19126753
references: Cell Res. 2011 Mar;21(3):435-41
references: 21321606
references: Genes Dev. 2012 Nov 15;26(22):2499-511
references: 23105005
references: Nat Struct Mol Biol. 2008 Nov;15(11):1176-83
references: 18953337
references: J Biol Chem. 2001 Jul 6;276(27):25309-17
references: 11316813
references: Nucleic Acids Res. 2010 Jun;38(11):3503-11
references: 20159995
references: Genes Dev. 2006 Nov 15;20(22):3089-103
references: 17085482
references: PLoS One. 2009;4(8):e6792
references: 19710927
references: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18303-8
references: 19822740
references: Science. 2010 Apr 2;328(5974):94-8
references: 20360108
references: Mol Cell Biol. 2006 Dec;26(24):9185-95
references: 17030614
references: Gene Expr Patterns. 2013 Mar-Apr;13(3-4):84-90
references: 23333759
references: Epigenetics Chromatin. 2013 Jun 04;6(1):15
references: 23735015
references: Cell. 2006 Jun 2;125(5):971-86
references: 16751105
references: Nature. 2013 Dec 5;504(7478):163-7
references: 24196706
references: Crit Rev Eukaryot Gene Expr. 2011;21(2):101-13
references: 22077150
references: Genome Res. 2003 Mar;13(3):476-84
references: 12618378
references: EMBO J. 2013 Jan 9;32(1):45-59
references: 23178591
references: Mol Cell. 2005 Aug 5;19(3):381-91
references: 16061184
references: EMBO Rep. 2012 Jan;13(1):60-7
references: 22056817
references: Genes Dev. 2005 Apr 1;19(7):815-26
references: 15774718