The H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity

English version České info

Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3. We demonstrate that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Consistent with its homology to UTX, UTX-1 regulates global levels of H3K27me2/3 in C. elegans. Surprisingly, we found that the catalytic activity is not required for the developmental function of this protein. Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL), and genetic analysis indicates that the defects associated with loss of UTX-1 are likely mediated by compromised SET-16/UTX-1 complex activity. Taken together, these results demonstrate that UTX-1 is required for many aspects of nematode development; but, unexpectedly, this function is independent of its enzymatic activity.

Vyšlo v časopise: The H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity. PLoS Genet 8(5): e32767. doi:10.1371/journal.pgen.1002647
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002647

Souhrn

Zdroje

1. StrahlBDAllisCD 2000 The language of covalent histone modifications. Nature 403 41 45

2. KouzaridesT 2007 Chromatin modifications and their function. Cell 128 693 705

3. BergerSL 2007 The complex language of chromatin regulation during transcription. Nature 447 407 412

4. TsukadaYFangJErdjument-BromageHWarrenMEBorchersCH 2006 Histone demethylation by a family of JmjC domain-containing proteins. Nature 439 811 816

5. CloosPAChristensenJAggerKHelinK 2008 Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev 22 1115 1140

6. AggerKCloosPAChristensenJPasiniDRoseS 2007 UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449 731 734

7. LeeMGVillaRTrojerPNormanJYanKP 2007 Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination. Science 318 447 450

8. SmithERLeeMGWinterBDrozNMEissenbergJC 2007 Drosophila UTX is a histone H3 Lys27 demethylase that colocalizes with the elongating form of RNA polymerase II. Mol Cell Biol 28 1041 1046

9. LanFBaylissPERinnJLWhetstineJRWangJK 2007 A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449 689 694

10. De SantaFTotaroMGProsperiniENotarbartoloSTestaG 2007 The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene Silencing. Cell 130 1083 1094

11. HongSChoYWYuLRYuHVeenstraTD 2007 Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA 104 18439 18444

12. FisherKSouthallSMWilsonJRPoulinGB 2010 Methylation and demethylation activities of a C. elegans MLL-like complex attenuate RAS signalling. Developmental biology 341 142 153

13. MauresTJGreerELHauswirthAGBrunetA 2011 The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging cell 10 980 990

14. JinCLiJGreenCDYuXTangX 2011 Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell metabolism 14 161 172

15. MohlerWASimskeJSWilliams-MassonEMHardinJDWhiteJG 1998 Dynamics and ultrastructure of developmental cell fusions in the Caenorhabditis elegans hypodermis. Current biology : CB 8 1087 1090

16. HendersonSTGaoDLambieEJKimbleJ 1994 lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development 120 2913 2924

17. SwigutTWysockaJ 2007 H3K27 demethylases, at long last. Cell 131 29 32

18. JinCLiJGreenCDYuXTangX 2011 Histone Demethylase UTX-1 Regulates C. elegans Life Span by Targeting the Insulin/IGF-1 Signaling Pathway. Cell metabolism 14 161 172

19. CloosPAChristensenJAggerKMaiolicaARappsilberJ 2006 The putative oncogene GASC1 demethylates tri -⁠ and dimethylated lysine 9 on histone H3. Nature 442 307 311

20. KloseRJYamaneKBaeYZhangDErdjument-BromageH 2006 The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442 312 316

21. ChangBChenYZhaoYBruickRK 2007 JMJD6 is a histone arginine demethylase. Science 318 444 447

22. IssaevaIZonisYRozovskaiaTOrlovskyKCroceCM 2007 Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol 27 1889 1903

23. ChoYWHongTHongSGuoHYuH 2007 PTIP associates with MLL3 -⁠ and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem 282 20395 20406

24. PatelSRKimDLevitanIDresslerGR 2007 The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev Cell 13 580 592

25. ShilatifardA 2008 Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Current opinion in cell biology 20 341 348

26. SimonetTDulermoRSchottSPalladinoF 2007 Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Developmental biology 312 367 383

27. AndersenECHorvitzHR 2007 Two C. elegans histone methyltransferases repress lin-3 EGF transcription to inhibit vulval development. Development 134 2991 2999

28. SeenundunSRampalliSLiuQCAzizAPaliiC 2010 UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis. The EMBO journal 29 1401 1411

29. AggerKCloosPARudkjaerLWilliamsKAndersenG 2009 The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene -⁠ and stress-induced senescence. Genes Dev 23 1171 1176

30. MillerSAMohnSEWeinmannAS 2010 Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Molecular cell 40 594 605

31. GreerELMauresTJHauswirthAGGreenEMLeemanDS 2010 Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466 383 387

32. XiaoYBedetCRobertVJSimonetTDunkelbargerS 2011 Caenorhabditis elegans chromatin-associated proteins SET-2 and ASH-2 are differentially required for histone H3 Lys 4 methylation in embryos and adult germ cells. Proceedings of the National Academy of Sciences of the United States of America 108 8305 8310

33. SolariFAhringerJ 2000 NURD-complex genes antagonise Ras-induced vulval development in Caenorhabditis elegans. Current biology : CB 10 223 226

34. LiebJDAlbrechtMRChuangPTMeyerBJ 1998 MIX-1: an essential component of the C. elegans mitotic machinery executes X chromosome dosage compensation. Cell 92 265 277

35. WangJKTsaiMCPoulinGAdlerASChenS 2010 The histone demethylase UTX enables RB-dependent cell fate control. Genes & development 24 327 332

36. LiTKellyWG 2011 A role for Set1/MLL-related components in epigenetic regulation of the Caenorhabditis elegans germ line. PLoS Genet 7 e1001349 doi:10.1371/journal.pgen.1001349

37. CapowskiEEMartinPGarvinCStromeS 1991 Identification of grandchildless loci whose products are required for normal germ-line development in the nematode Caenorhabditis elegans. Genetics 129 1061 1072

38. PaulsenJECapowskiEEStromeS 1995 Phenotypic and molecular analysis of mes-3, a maternal-effect gene required for proliferation and viability of the germ line in C. elegans. Genetics 141 1383 1398

39. KellyWGFireA 1998 Chromatin silencing and the maintenance of a functional germline in Caenorhabditis elegans. Development 125 2451 2456

40. HoldemanRNehrtSStromeS 1998 MES-2, a maternal protein essential for viability of the germline in Caenorhabditis elegans, is homologous to a Drosophila Polycomb group protein. Development 125 2457 2467

41. KorfIFanYStromeS 1998 The Polycomb group in Caenorhabditis elegans and maternal control of germline development. Development 125 2469 2478

42. BenderLBCaoRZhangYStromeS 2004 The MES-2/MES-3/MES-6 complex and regulation of histone H3 methylation in C. elegans. Curr Biol 14 1639 1643

43. BenderLBSuhJCarrollCRFongYFingermanIM 2006 MES-4: an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in the C. elegans germ line. Development 133 3907 3917

44. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94

45. TimmonsLCourtDLFireA 2001 Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263 103 112

46. KragCMalmbergEKSalciniAE 2010 PI3KC2alpha, a class II PI3K, is required for dynamin-independent internalization pathways. Journal of cell science 123 4240 4250

47. FinneyMRuvkunG 1990 The unc-86 gene product couples cell lineage and cell identity in C. elegans. Cell 63 895 905

48. VandammeJVolkelPRosnobletCLe FaouPAngrandPO 2011 Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. Molecular & cellular proteomics : MCP 10 M110 002642