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PMID: 19026781 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms.

Molecular cell ·Vol. 32 ·No. 4 ·2008-11-21 ·Pages 503-18

Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, Dynlacht BD, Reinberg D

Abstract

Polycomb group proteins are critical to maintaining gene repression established during Drosophila development. Part of this group forms the PRC2 complex containing Ez that catalyzes di- and trimethylation of histone H3 lysine 27 (H3K37me2/3), marks repressive to transcription. We report that the mammalian homologs Ezh1 and Ezh2 form similar PRC2 complexes but exhibit contrasting repressive roles. While PRC2-Ezh2 catalyzes H3K27me2/3 and its knockdown affects global H3K27me2/3 levels, PRC2-Ezh1 performs this function weakly. In accordance, Ezh1 knockdown was ineffectual on global H3K27me2/3 levels. Instead, PRC2-Ezh1 directly and robustly represses transcription from chromatinized templates and compacts chromatin in the absence of the methyltransferase cofactor SAM, as evidenced by electron microscopy. Ezh1 targets a subset of Ezh2 genes, yet Ezh1 is more abundant in nonproliferative adult organs while Ezh2 expression is tightly associated with proliferation, as evidenced when analyzing aging mouse kidney. These results might reflect subfunctionalization of a PcG protein during evolution.

MeSH Terms
Animals Baculoviridae/genetics Cell Line Cell Line, Tumor Chromatin/genetics,isolation & purification,metabolism,ultrastructure Chromatin Immunoprecipitation DNA-Binding Proteins/genetics,metabolism Enhancer of Zeste Homolog 2 Protein Genes, Reporter HeLa Cells Histone-Lysine N-Methyltransferase/genetics,metabolism Humans Immunohistochemistry Jurkat Cells Kidney/cytology Luciferases/metabolism Mice Mutation NIH 3T3 Cells Polycomb Repressive Complex 2 Promoter Regions, Genetic Recombinant Proteins/metabolism Repressor Proteins/metabolism Transcription Factors/genetics,metabolism Transfection
Chemicals
Chromatin DNA-Binding Proteins Recombinant Proteins Repressor Proteins Transcription Factors Luciferases EZH1 protein, human EZH2 protein, human Enhancer of Zeste Homolog 2 Protein Ezh1 protein, mouse Ezh2 protein, mouse Histone-Lysine N-Methyltransferase Polycomb Repressive Complex 2
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Margueron Raphael
Department of Biochemistry, New York University Medical School, 522 First Avenue, New York, NY 10016, USA.
Li Guohong
Sarma Kavitha
Blais Alexandre
Zavadil Jiri
Woodcock Christopher L
Dynlacht Brian D
Reinberg Danny
References (69)
69 references, click to expand
  1. Structural basis of EZH2 recognition by EED.
    Structure. 2007 Oct;15(10):1306-15 PMID: 17937919
  2. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing.
    EMBO J. 2006 Jul 12;25(13):3110-22 PMID: 16763550
  3. Control of developmental regulators by Polycomb in human embryonic stem cells.
    Cell. 2006 Apr 21;125(2):301-13 PMID: 16630818
  4. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex.
    Cell. 2002 Oct 18;111(2):197-208 PMID: 12408864
  5. 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
  6. 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
  7. Reconstitution and transcriptional analysis of chromatin in vitro.
    Methods Enzymol. 2004;377:460-74 PMID: 14979045
  8. Nucleosome arrays reveal the two-start organization of the chromatin fiber.
    Science. 2004 Nov 26;306(5701):1571-3 PMID: 15567867
  9. Polycomb complexes repress developmental regulators in murine embryonic stem cells.
    Nature. 2006 May 18;441(7091):349-53 PMID: 16625203
  10. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin.
    Mol Cell. 2002 Jun;9(6):1201-13 PMID: 12086618
  11. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing.
    Mol Cell. 2007 Nov 30;28(4):665-76 PMID: 18042460
  12. 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
  13. Nucleosomal DNA regulates the core-histone-binding subunit of the human Hat1 acetyltransferase.
    Curr Biol. 1998 Jan 15;8(2):96-108 PMID: 9427644
  14. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement.
    Nat Immunol. 2003 Feb;4(2):124-31 PMID: 12496962
  15. Isolation and characterization of Suv39h2, a second histone H3 methyltransferase gene that displays testis-specific expression.
    Mol Cell Biol. 2000 Dec;20(24):9423-33 PMID: 11094092
  16. Structural basis of histone H4 recognition by p55.
    Genes Dev. 2008 May 15;22(10):1313-8 PMID: 18443147
  17. L3MBTL1, a histone-methylation-dependent chromatin lock.
    Cell. 2007 Jun 1;129(5):915-28 PMID: 17540172
  18. An initial blueprint for myogenic differentiation.
    Genes Dev. 2005 Mar 1;19(5):553-69 PMID: 15706034
  19. Cell-specific regulation of androgen receptor phosphorylation in vivo.
    J Biol Chem. 2005 Dec 9;280(49):40916-24 PMID: 16210317
  20. Electron microscope visualization of chromatin and other DNA-protein complexes.
    Annu Rev Biophys Bioeng. 1978;7:19-35 PMID: 78683
  21. Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos.
    Dev Cell. 2008 Nov;15(5):668-79 PMID: 18848501
  22. The product of the murine homolog of the Drosophila extra sex combs gene displays transcriptional repressor activity.
    Mol Cell Biol. 1997 Aug;17(8):4707-17 PMID: 9234727
  23. Genome-wide analysis of Polycomb targets in Drosophila melanogaster.
    Nat Genet. 2006 Jun;38(6):700-5 PMID: 16732288
  24. Polycomb/Trithorax response elements and epigenetic memory of cell identity.
    Development. 2007 Jan;134(2):223-32 PMID: 17185323
  25. MAP kinase-mediated c-fos regulation relies on a histone acetylation relay switch.
    Mol Cell. 2008 Mar 28;29(6):780-5 PMID: 18374651
  26. Role of histone H3 lysine 27 methylation in Polycomb-group silencing.
    Science. 2002 Nov 1;298(5595):1039-43 PMID: 12351676
  27. Loss of HCF-1-chromatin association precedes temperature-induced growth arrest of tsBN67 cells.
    Mol Cell Biol. 2001 Jun;21(11):3820-9 PMID: 11340173
  28. Role of histone H2A ubiquitination in Polycomb silencing.
    Nature. 2004 Oct 14;431(7010):873-8 PMID: 15386022
  29. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions.
    Genes Dev. 2006 May 1;20(9):1123-36 PMID: 16618801
  30. Polycomb Group proteins: an evolutionary perspective.
    Trends Genet. 2007 Oct;23(10):494-502 PMID: 17825942
  31. The Polycomb-group protein ENX-2 interacts with ZAP-70.
    Immunol Lett. 2003 Mar 3;86(1):57-61 PMID: 12600746
  32. Subunit contributions to histone methyltransferase activities of fly and worm polycomb group complexes.
    Mol Cell Biol. 2005 Aug;25(16):6857-68 PMID: 16055700
  33. Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation.
    Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1859-64 PMID: 15684044
  34. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.
    Cell. 2007 Jun 29;129(7):1311-23 PMID: 17604720
  35. A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities.
    Genes Dev. 2006 May 1;20(9):1110-22 PMID: 16618800
  36. Stabilization of chromatin structure by PRC1, a Polycomb complex.
    Cell. 1999 Jul 9;98(1):37-46 PMID: 10412979
  37. Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy.
    Mol Cancer Ther. 2003 Jan;2(1):113-21 PMID: 12533679
  38. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3.
    Mol Cell. 2004 Apr 23;14(2):183-93 PMID: 15099518
  39. Accumulation of malignant renal stem cells is associated with epigenetic changes in normal renal progenitor genes.
    Stem Cells. 2008 Jul;26(7):1808-17 PMID: 18467665
  40. Chromatin compaction by a polycomb group protein complex.
    Science. 2004 Nov 26;306(5701):1574-7 PMID: 15567868
  41. 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
  42. The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans.
    Mol Cell Biol. 2002 Sep;22(17):6070-8 PMID: 12167701
  43. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter.
    Cell. 2003 Dec 12;115(6):751-63 PMID: 14675539
  44. 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
  45. Genome regulation by polycomb and trithorax proteins.
    Cell. 2007 Feb 23;128(4):735-45 PMID: 17320510
  46. High histone acetylation and decreased polycomb repressive complex 2 member levels regulate gene specific transcriptional changes during early embryonic stem cell differentiation induced by retinoic acid.
    Stem Cells. 2007 Sep;25(9):2191-9 PMID: 17525233
  47. Multiple modes of interaction between the methylated DNA binding protein MeCP2 and chromatin.
    Mol Cell Biol. 2007 Feb;27(3):864-77 PMID: 17101771
  48. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast.
    J Clin Oncol. 2006 Jan 10;24(2):268-73 PMID: 16330673
  49. Differential expression of human Polycomb group proteins in various tissues and cell types.
    J Cell Biochem Suppl. 2001;Suppl 36:129-43 PMID: 11455578
  50. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability.
    Cell. 2001 Nov 2;107(3):323-37 PMID: 11701123
  51. Polycomb group protein-associated chromatin is reproduced in post-mitotic G1 phase and is required for S phase progression.
    J Biol Chem. 2008 Jul 4;283(27):18905-15 PMID: 18453536
  52. Cloning and expression of a human/mouse Polycomb group gene, ENX-2/Enx-2.
    Biochim Biophys Acta. 1998 Jan 21;1395(2):151-8 PMID: 9473645
  53. Splitting pairs: the diverging fates of duplicated genes.
    Nat Rev Genet. 2002 Nov;3(11):827-37 PMID: 12415313
  54. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II.
    Cell. 2006 May 19;125(4):703-17 PMID: 16713563
  55. Retinoid regulated association of transcriptional co-regulators and the polycomb group protein SUZ12 with the retinoic acid response elements of Hoxa1, RARbeta(2), and Cyp26A1 in F9 embryonal carcinoma cells.
    J Mol Biol. 2007 Sep 14;372(2):298-316 PMID: 17663992
  56. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster.
    Nat Genet. 2006 Jun;38(6):694-9 PMID: 16628213
  57. Characterization of EZH1, a human homolog of Drosophila Enhancer of zeste near BRCA1.
    Genomics. 1996 Oct 15;37(2):161-71 PMID: 8921387
  58. 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
  59. Hierarchical recruitment of polycomb group silencing complexes.
    Mol Cell. 2004 Jun 4;14(5):637-46 PMID: 15175158
  60. Suz12 binds to silenced regions of the genome in a cell-type-specific manner.
    Genome Res. 2006 Jul;16(7):890-900 PMID: 16751344
  61. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.
    Mol Cell. 2004 Oct 8;16(1):93-105 PMID: 15469825
  62. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.
    EMBO J. 2003 Oct 15;22(20):5323-35 PMID: 14532106
  63. The polycomb group protein Suz12 is required for embryonic stem cell differentiation.
    Mol Cell Biol. 2007 May;27(10):3769-79 PMID: 17339329
  64. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.
    Genes Dev. 2004 Jun 1;18(11):1251-62 PMID: 15145825
  65. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo.
    Mol Cell Biol. 2008 Apr;28(8):2718-31 PMID: 18285464
  66. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity.
    EMBO J. 2004 Oct 13;23(20):4061-71 PMID: 15385962
  67. The polycomb-group gene Ezh2 is required for early mouse development.
    Mol Cell Biol. 2001 Jul;21(13):4330-6 PMID: 11390661
  68. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin.
    Mol Cell Biol. 2006 Apr;26(7):2560-9 PMID: 16537902
  69. The polycomb group protein EZH2 is required for mammalian circadian clock function.
    J Biol Chem. 2006 Jul 28;281(30):21209-21215 PMID: 16717091
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2008.11.004
Published
2008-11-21
Pages
503-18
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3641558
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · R01 GM064844 · United States
NIGMS NIH HHS · GM64844 · United States
Databases
GEO
GSE13467
External Links
PubMed source DOI: 10.1016/j.molcel.2008.11.004 PMC Full Text View journal details
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