Histone H3K9 Trimethylase Eggless Controls Germline Stem Cell Maintenance and Differentiation

English version České info

Epigenetic regulation plays critical roles in the regulation of cell proliferation, fate determination, and survival. It has been shown to control self-renewal and lineage differentiation of embryonic stem cells. However, epigenetic regulation of adult stem cell function remains poorly defined. Drosophila ovarian germline stem cells (GSCs) are a productive adult stem cell system for revealing regulatory mechanisms controlling self-renewal and differentiation. In this study, we show that Eggless (Egg), a H3K9 methyltransferase in Drosophila, is required in GSCs for controlling self-renewal and in escort cells for regulating germ cell differentiation. egg mutant ovaries primarily exhibit germ cell differentiation defects in young females and gradually lose GSCs with time, indicating that Egg regulates both germ cell maintenance and differentiation. Marked mutant egg GSCs lack expression of trimethylated H3K9 (H3k9me3) and are rapidly lost from the niche, but their mutant progeny can still differentiate into 16-cell cysts, indicating that Egg is required intrinsically to control GSC self-renewal but not differentiation. Interestingly, BMP-mediated transcriptional repression of differentiation factor bam in marked egg mutant GSCs remains normal, indicating that Egg is dispensable for BMP signaling in GSCs. Normally, Bam and Bgcn interact with each other to promote GSC differentiation. Interestingly, marked double mutant egg bgcn GSCs are still lost, but their progeny are able to differentiate into 16-cell cysts though bgcn mutant GSCs normally do not differentiate, indicating that Egg intrinsically controls GSC self-renewal through repressing a Bam/Bgcn-independent pathway. Surprisingly, RNAi-mediated egg knockdown in escort cells leads to their gradual loss and a germ cell differentiation defect. The germ cell differentiation defect is at least in part attributed to an increase in BMP signaling in the germ cell differentiation niche. Therefore, this study has revealed the essential roles of histone H3K9 trimethylation in controlling stem cell maintenance and differentiation through distinct mechanisms.

Vyšlo v časopise: Histone H3K9 Trimethylase Eggless Controls Germline Stem Cell Maintenance and Differentiation. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002426
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002426

Souhrn

Zdroje

1. LessardJACrabtreeGR 2010 Chromatin regulatory mechanisms in pluripotency. Annu Rev Cell Dev Biol 26 503 532

2. AdamoASeseBBoueSCastanoJParamonovI 2011 LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol 13 652 660

3. LohYHZhangWChenXGeorgeJNgHH 2007 Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev 21 2545 2557

4. FazzioTGHuffJTPanningB 2008 An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 134 162 174

5. PasiniDHansenKHChristensenJAggerKCloosPA 2008 Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev 22 1345 1355

6. ShenXKimWFujiwaraYSimonMDLiuY 2009 Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139 1303 1314

7. BuszczakMSpradlingAC 2006 Searching chromatin for stem cell identity. Cell 125 233 236

8. BilodeauSKageyMHFramptonGMRahlPBYoungRA 2009 SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 23 2484 2489

9. KirillyDXieT 2007 The Drosophila ovary: an active stem cell community. Cell Res 17 15 25

10. XieTSpradlingA 2001 The Drosophila Ovary: An In Vivo Stem Cell System. MarshakDRGardnerRLGottliebD Stem Cell Biology Cold Spring Harbor, , N.Y. Cold Spring Harbor Laboratory Press 129 148

11. XieTSpradlingAC 1998 decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary. Cell 94 251 260

12. XieTSpradlingAC 2000 A niche maintaining germ line stem cells in the Drosophila ovary. Science 290 328 330

13. SongXWongMDKawaseEXiRDingBC 2004 Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development 131 1353 1364

14. ChenDMcKearinD 2003 Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells. Curr Biol 13 1786 1791

15. XiRXieT 2005 Stem cell self-renewal controlled by chromatin remodeling factors. Science 310 1487 1489

16. MainesJZParkJKWilliamsMMcKearinDM 2007 Stonewalling Drosophila stem cell differentiation by epigenetic controls. Development 134 1471 1479

17. Di StefanoLJiJYMoonNSHerrADysonN 2007 Mutation of Drosophila Lsd1 disrupts H3-K4 methylation, resulting in tissue-specific defects during development. Curr Biol 17 808 812

18. EliazerSShalabyNABuszczakM 2011 Loss of lysine-specific demethylase 1 nonautonomously causes stem cell tumors in the Drosophila ovary. Proc Natl Acad Sci U S A 108 7064 7069

19. BannisterAJZegermanPPartridgeJFMiskaEAThomasJO 2001 Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410 120 124

20. EbertASchottaGLeinSKubicekSKraussV 2004 Su(var) genes regulate the balance between euchromatin and heterochromatin in Drosophila. Genes Dev 18 2973 2983

21. SchottaGEbertAKraussVFischerAHoffmannJ 2002 Central role of Drosophila SU(VAR)3-9 in histone H3-K9 methylation and heterochromatic gene silencing. Embo J 21 1121 1131

22. MisJNerSSGrigliattiTA 2006 Identification of three histone methyltransferases in Drosophila: dG9a is a suppressor of PEV and is required for gene silencing. Mol Genet Genomics 275 513 526

23. StabellMEskelandRBjorkmoMLarssonJAalenRB 2006 The Drosophila G9a gene encodes a multi-catalytic histone methyltransferase required for normal development. Nucleic Acids Res 34 4609 4621

24. Brower-TolandBRiddleNCJiangHHuisingaKLElginSC 2009 Multiple SET methyltransferases are required to maintain normal heterochromatin domains in the genome of Drosophila melanogaster. Genetics 181 1303 1319

25. SeumCReoEPengHRauscherFJ3rdSpiererP 2007 Drosophila SETDB1 is required for chromosome 4 silencing. PLoS Genet 3 e76 doi:10.1371/journal.pgen.0030076

26. TzengTYLeeCHChanLWShenCK 2007 Epigenetic regulation of the Drosophila chromosome 4 by the histone H3K9 methyltransferase dSETDB1. Proc Natl Acad Sci U S A 104 12691 12696

27. YoonJLeeKSParkJSYuKPaikSG 2008 dSETDB1 and SU(VAR)3-9 sequentially function during germline-stem cell differentiation in Drosophila melanogaster. PLoS ONE 3 e2234 doi:10.1371/journal.pone.0002234

28. CloughEMoonWWangSSmithKHazelriggT 2007 Histone methylation is required for oogenesis in Drosophila. Development 134 157 165

29. KochCMHonemann-CapitoMEgger-AdamDWodarzA 2009 Windei, the Drosophila homolog of mAM/MCAF1, is an essential cofactor of the H3K9 methyl transferase dSETDB1/Eggless in germ line development. PLoS Genet 5 e1000644 doi:10.1371/journal.pgen.1000644

30. LaskoPFAshburnerM 1988 The product of the Drosophila gene vasa is very similar to eukaryotic initiation factor-4A. Nature 335 611 617

31. HayBJanLYJanYN 1988 A protein component of Drosophila polar granules is encoded by vasa and has extensive sequence similarity to ATP-dependent helicases. Cell 55 577 587

32. LinHYueLSpradlingAC 1994 The Drosophila fusome, a germline-specific organelle, contains membrane skeletal proteins and functions in cyst formation. Development 120 947 956

33. SongXZhuCHDoanCXieT 2002 Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 296 1855 1857

34. NiJQZhouRCzechBLiuLPHolderbaumL 2011 A genome-scale shRNA resource for transgenic RNAi in Drosophila. Nat Methods 8 405 407

35. CasanuevaMOFergusonEL 2004 Germline stem cell number in the Drosophila ovary is regulated by redundant mechanisms that control Dpp signaling. Development 131 1881 1890

36. KaiTSpradlingA 2003 An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. Proc Natl Acad Sci U S A 100 4633 4638

37. McKearinDMSpradlingAC 1990 bag-of-marbles: a Drosophila gene required to initiate both male and female gametogenesis. Genes Dev 4 2242 2251

38. OhlsteinBMcKearinD 1997 Ectopic expression of the Drosophila Bam protein eliminates oogenic germline stem cells. Development 124 3651 3662

39. OhlsteinBLavoieCAVefOGateffEMcKearinDM 2000 The Drosophila cystoblast differentiation factor, benign gonial cell neoplasm, is related to DExH-box proteins and interacts genetically with bag-of-marbles. Genetics 155 1809 1819

40. JinZKirillyDWengCKawaseESongX 2008 Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. Cell Stem Cell 2 39 49

41. ChenSKanekoSMaXChenXIpYT 2010 Lissencephaly-1 controls germline stem cell self-renewal through modulating bone morphogenetic protein signaling and niche adhesion. Proc Natl Acad Sci U S A 107 19939 19944

42. LiuMLimTMCaiY 2010 The Drosophila female germline stem cell lineage acts to spatially restrict DPP function within the niche. Sci Signal 3 ra57

43. GuoZWangZ 2009 The glypican Dally is required in the niche for the maintenance of germline stem cells and short-range BMP signaling in the Drosophila ovary. Development 136 3627 3635

44. AkiyamaTKamimuraKFirkusCTakeoSShimmiO 2008 Dally regulates Dpp morphogen gradient formation by stabilizing Dpp on the cell surface. Dev Biol 313 408 419

45. SchultzCWoodCGJonesDLTazukeSIFullerMT 2002 Signaling from germ cells mediated by the rhomboid homolog stet organizes encapsulation by somatic support cells. Development 129 4523 4534

46. MargolisJSpradlingA 1995 Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 121 3797 3807

47. PennettaGPauliD 1998 The Drosophila Sin3 gene encodes a widely distributed transcription factor essential for embryonic viability. Dev Genes Evol 208 531 536

48. MullerJHartCMFrancisNJVargasMLSenguptaA 2002 Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111 197 208

49. EissenbergJCMorrisGDReuterGHartnettT 1992 The heterochromatin-associated protein HP-1 is an essential protein in Drosophila with dosage-dependent effects on position-effect variegation. Genetics 131 345 352

50. EissenbergJCJamesTCFoster-HartnettDMHartnettTNganV 1990 Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster. Proc Natl Acad Sci U S A 87 9923 9927

51. LachnerMO'CarrollDReaSMechtlerKJenuweinT 2001 Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410 116 120

52. KirillyDWangSXieT 2011 Self-maintained escort cells form a germline stem cell differentiation niche. Development 138 5087 5097

53. ChenDMcKearinD 2005 Gene circuitry controlling a stem cell niche. Curr Biol 15 179 184

54. SzakmaryACoxDNWangZLinH 2005 Regulatory Relationship among piwi, pumilio, and bag-of-marbles in Drosophila Germline Stem Cell Self-Renewal and Differentiation. Curr Biol 15 171 178

55. XiRDoanCLiuDXieT 2005 Pelota controls self-renewal of germline stem cells by repressing a Bam-independent differentiation pathway. Development 132 5365 5374

56. RanganPMaloneCDNavarroCNewboldSPHayesPS 2011 piRNA Production Requires Heterochromatin Formation in Drosophila. Curr Biol 21 1373 1379

57. KlattenhoffCBratuDPMcGinnis-SchultzNKoppetschBSCookHA 2007 Drosophila rasiRNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response. Dev Cell 12 45 55

58. KirillyDWangSXieT 2011 Self-Maintained Escort Cells Form a Germline Stem Cell Differentiation Niche. Development (In press)

59. DecottoESpradlingAC 2005 The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev Cell 9 501 510

60. TsuneizumiKNakayamaTKamoshidaYKornbergTBChristianJL 1997 Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389 627 631

61. ChenDMcKearinDM 2003 A discrete transcriptional silencer in the bam gene determines asymmetric division of the Drosophila germline stem cell. Development 130 1159 1170

62. Van DorenMWilliamsonALLehmannR 1998 Regulation of zygotic gene expression in Drosophila primordial germ cells. Curr Biol 8 243 246

63. ManseauLBaradaranABrowerDBudhuAElefantF 1997 GAL4 enhancer traps expressed in the embryo, larval brain, imaginal discs, and ovary of Drosophila. Dev Dyn 209 310 322

64. HayBAWolffTRubinGM 1994 Expression of baculovirus P35 prevents cell death in Drosophila. Development 120 2121 2129