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PMID: 19026780 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency.

Molecular cell ·Vol. 32 ·No. 4 ·2008-11-21 ·Pages 491-502

Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC, Orkin SH

Abstract

Trimethylation on H3K27 (H3K27me3) mediated by Polycomb repressive complex 2 (PRC2) has been linked to embryonic stem cell (ESC) identity and pluripotency. EZH2, the catalytic subunit of PRC2, has been reported as the sole histone methyltransferase that methylates H3K27 and mediates transcriptional silencing. Analysis of Ezh2(-/-) ESCs suggests existence of an additional enzyme(s) catalyzing H3K27 methylation. We have identified EZH1, a homolog of EZH2 that is physically present in a noncanonical PRC2 complex, as an H3K27 methyltransferase in vivo and in vitro. EZH1 colocalizes with the H3K27me3 mark on chromatin and preferentially preserves this mark on development-related genes in Ezh2(-/-) ESCs. Depletion of Ezh1 in cells lacking Ezh2 abolishes residual methylation on H3K27 and derepresses H3K27me3 target genes, demonstrating a role of EZH1 in safeguarding ESC identity. Ezh1 partially complements Ezh2 in executing pluripotency during ESC differentiation, suggesting that cell-fate transitions require epigenetic specificity.

MeSH Terms
Animals Cell Differentiation Cell Line DNA-Binding Proteins/metabolism Enhancer of Zeste Homolog 2 Protein Genes, Regulator Histone-Lysine N-Methyltransferase Histones/genetics,metabolism Lysine/genetics,metabolism Methylation Mice Models, Biological Polycomb Repressive Complex 2 Stem Cells/metabolism Transcription Factors/metabolism
Chemicals
DNA-Binding Proteins Histones Transcription Factors Enhancer of Zeste Homolog 2 Protein Ezh1 protein, mouse Ezh2 protein, mouse Histone-Lysine N-Methyltransferase Polycomb Repressive Complex 2 Lysine
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Shen Xiaohua
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Liu Yingchun
Hsu Yu-Jung
Fujiwara Yuko
Kim Jonghwan
Mao Xiaohong
Yuan Guo-Cheng
Orkin Stuart H
References (47)
47 references, click to expand
  1. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement.
    Nat Immunol. 2003 Feb;4(2):124-31 PMID: 12496962
  2. The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation.
    Nat Cell Biol. 2006 Feb;8(2):195-202 PMID: 16415857
  3. Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation.
    Development. 2003 Sep;130(17):4217-27 PMID: 12874139
  4. The MES-2/MES-3/MES-6 complex and regulation of histone H3 methylation in C. elegans.
    Curr Biol. 2004 Sep 21;14(18):1639-43 PMID: 15380065
  5. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex.
    Cell. 2002 Oct 18;111(2):197-208 PMID: 12408864
  6. Polycomb silencing mechanisms and the management of genomic programmes.
    Nat Rev Genet. 2007 Jan;8(1):9-22 PMID: 17173055
  7. The N terminus of Drosophila ESC binds directly to histone H3 and is required for E(Z)-dependent trimethylation of H3 lysine 27.
    Mol Cell Biol. 2007 Mar;27(6):2014-26 PMID: 17210640
  8. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.
    Mol Cell. 2004 Jul 2;15(1):57-67 PMID: 15225548
  9. Nucleosome binding and histone methyltransferase activity of Drosophila PRC2.
    EMBO Rep. 2005 Apr;6(4):348-53 PMID: 15776017
  10. Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres.
    EMBO J. 1997 Jun 2;16(11):3219-32 PMID: 9214638
  11. Polycomb complexes repress developmental regulators in murine embryonic stem cells.
    Nature. 2006 May 18;441(7091):349-53 PMID: 16625203
  12. Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase Mll2.
    Mol Biol Cell. 2007 Jun;18(6):2356-66 PMID: 17429066
  13. Model-based analysis of tiling-arrays for ChIP-chip.
    Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12457-62 PMID: 16895995
  14. Interaction of mouse polycomb-group (Pc-G) proteins Enx1 and Enx2 with Eed: indication for separate Pc-G complexes.
    Mol Cell Biol. 1998 Jun;18(6):3572-9 PMID: 9584197
  15. The polycomb group protein Suz12 is required for embryonic stem cell differentiation.
    Mol Cell Biol. 2007 May;27(10):3769-79 PMID: 17339329
  16. Stem cells and cancer; the polycomb connection.
    Cell. 2004 Aug 20;118(4):409-18 PMID: 15315754
  17. Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm.
    Dev Biol. 2003 Jun 1;258(1):91-104 PMID: 12781685
  18. An extended transcriptional network for pluripotency of embryonic stem cells.
    Cell. 2008 Mar 21;132(6):1049-61 PMID: 18358816
  19. Role of histone H3 lysine 27 methylation in Polycomb-group silencing.
    Science. 2002 Nov 1;298(5595):1039-43 PMID: 12351676
  20. Core transcriptional regulatory circuitry in human embryonic stem cells.
    Cell. 2005 Sep 23;122(6):947-56 PMID: 16153702
  21. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3.
    J Biol Chem. 2001 Jul 6;276(27):25309-17 PMID: 11316813
  22. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice.
    Development. 2007 Jul;134(14):2627-38 PMID: 17567665
  23. The eed mutation disrupts anterior mesoderm production in mice.
    Development. 1995 Feb;121(2):273-85 PMID: 7768172
  24. Control of developmental regulators by Polycomb in human embryonic stem cells.
    Cell. 2006 Apr 21;125(2):301-13 PMID: 16630818
  25. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation.
    Genes Dev. 2004 Nov 1;18(21):2627-38 PMID: 15520282
  26. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development.
    Development. 2003 Sep;130(18):4235-48 PMID: 12900441
  27. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.
    Genes Dev. 2002 Nov 15;16(22):2893-905 PMID: 12435631
  28. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation.
    Curr Biol. 2005 May 24;15(10):942-7 PMID: 15916951
  29. The Drosophila esc and E(z) proteins are direct partners in polycomb group-mediated repression.
    Mol Cell Biol. 1998 May;18(5):2825-34 PMID: 9566901
  30. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites.
    Cell. 2002 Oct 18;111(2):185-96 PMID: 12408863
  31. The SWI/SNF complex--chromatin and cancer.
    Nat Rev Cancer. 2004 Feb;4(2):133-42 PMID: 14964309
  32. An essential switch in subunit composition of a chromatin remodeling complex during neural development.
    Neuron. 2007 Jul 19;55(2):201-15 PMID: 17640523
  33. High-resolution profiling of histone methylations in the human genome.
    Cell. 2007 May 18;129(4):823-37 PMID: 17512414
  34. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development.
    Development. 2006 Apr;133(8):1423-32 PMID: 16540515
  35. Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency.
    Stem Cells. 2008 Jun;26(6):1496-505 PMID: 18403752
  36. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  37. Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation.
    Mol Biol Cell. 2005 Apr;16(4):2018-27 PMID: 15703208
  38. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.
    Genes Dev. 2007 Mar 1;21(5):525-30 PMID: 17344414
  39. Embryonic stem cell differentiation: emergence of a new era in biology and medicine.
    Genes Dev. 2005 May 15;19(10):1129-55 PMID: 15905405
  40. A protein interaction network for pluripotency of embryonic stem cells.
    Nature. 2006 Nov 16;444(7117):364-8 PMID: 17093407
  41. Concise review: roles of polycomb group proteins in development and disease: a stem cell perspective.
    Stem Cells. 2007 Oct;25(10):2498-510 PMID: 17600113
  42. How is pluripotency determined and maintained?
    Development. 2007 Feb;134(4):635-46 PMID: 17215298
  43. The diverse functions of histone lysine methylation.
    Nat Rev Mol Cell Biol. 2005 Nov;6(11):838-49 PMID: 16261189
  44. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo.
    Mol Cell Biol. 2008 Apr;28(8):2718-31 PMID: 18285464
  45. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity.
    EMBO J. 2004 Oct 13;23(20):4061-71 PMID: 15385962
  46. The polycomb-group gene Ezh2 is required for early mouse development.
    Mol Cell Biol. 2001 Jul;21(13):4330-6 PMID: 11390661
  47. The proteasome restricts permissive transcription at tissue-specific gene loci in embryonic stem cells.
    Cell. 2006 Dec 29;127(7):1375-88 PMID: 17190601
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2008.10.016
Published
2008-11-21
Pages
491-502
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC2630502
Subset
IM
Grants
Howard Hughes Medical Institute · United States
Databases
GEO
GSE12982
External Links
PubMed source DOI: 10.1016/j.molcel.2008.10.016 PMC Full Text View journal details
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