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H3K9me-Independent Gene Silencing in Fission Yeast Heterochromatin by Clr5 and Histone Deacetylases


Nucleosomes in heterochromatic regions bear histone modifications that distinguish them from euchromatic nucleosomes. Among those, histone H3 lysine 9 methylation (H3K9me) and hypoacetylation have been evolutionarily conserved and are found in both multicellular eukaryotes and single-cell model organisms such as fission yeast. In spite of numerous studies, the relative contributions of the various heterochromatic histone marks to the properties of heterochromatin remain largely undefined. Here, we report that silencing of the fission yeast mating-type cassettes, which are located in a well-characterized heterochromatic region, is hardly affected in cells lacking the H3K9 methyltransferase Clr4. We document the existence of a pathway parallel to H3K9me ensuring gene repression in the absence of Clr4 and identify a silencing factor central to this pathway, Clr5. We find that Clr5 controls gene expression at multiple chromosomal locations in addition to affecting the mating-type region. The histone deacetylase Clr6 acts in the same pathway as Clr5, at least for its effects in the mating-type region, and on a subset of other targets, notably a region recently found to be prone to neo-centromere formation. The genomic targets of Clr5 also include Ste11, a master regulator of sexual differentiation. Hence Clr5, like the multi-functional Atf1 transcription factor which also modulates chromatin structure in the mating-type region, controls sexual differentiation and genome integrity at several levels. Globally, our results point to histone deacetylases as prominent repressors of gene expression in fission yeast heterochromatin. These deacetylases can act in concert with, or independently of, the widely studied H3K9me mark to influence gene silencing at heterochromatic loci.


Vyšlo v časopise: H3K9me-Independent Gene Silencing in Fission Yeast Heterochromatin by Clr5 and Histone Deacetylases. PLoS Genet 7(1): e32767. doi:10.1371/journal.pgen.1001268
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001268

Souhrn

Nucleosomes in heterochromatic regions bear histone modifications that distinguish them from euchromatic nucleosomes. Among those, histone H3 lysine 9 methylation (H3K9me) and hypoacetylation have been evolutionarily conserved and are found in both multicellular eukaryotes and single-cell model organisms such as fission yeast. In spite of numerous studies, the relative contributions of the various heterochromatic histone marks to the properties of heterochromatin remain largely undefined. Here, we report that silencing of the fission yeast mating-type cassettes, which are located in a well-characterized heterochromatic region, is hardly affected in cells lacking the H3K9 methyltransferase Clr4. We document the existence of a pathway parallel to H3K9me ensuring gene repression in the absence of Clr4 and identify a silencing factor central to this pathway, Clr5. We find that Clr5 controls gene expression at multiple chromosomal locations in addition to affecting the mating-type region. The histone deacetylase Clr6 acts in the same pathway as Clr5, at least for its effects in the mating-type region, and on a subset of other targets, notably a region recently found to be prone to neo-centromere formation. The genomic targets of Clr5 also include Ste11, a master regulator of sexual differentiation. Hence Clr5, like the multi-functional Atf1 transcription factor which also modulates chromatin structure in the mating-type region, controls sexual differentiation and genome integrity at several levels. Globally, our results point to histone deacetylases as prominent repressors of gene expression in fission yeast heterochromatin. These deacetylases can act in concert with, or independently of, the widely studied H3K9me mark to influence gene silencing at heterochromatic loci.


Zdroje

1. KlarAJ

2007 Lessons learned from studies of fission yeast mating-type switching and silencing. Annu Rev Genet 41 213 236

2. KellyM

BurkeJ

SmithM

KlarA

BeachD

1988 Four mating-type genes control sexual differentiation in the fission yeast. EMBO J 7 1537 1547

3. GrewalSIS

BonaduceMJ

KlarAJS

1998 Histone deacetylase homologs regulate epigenetic inheritance of transcriptional silencing and chromosome segregation in fission yeast. Genetics 150 563 576

4. BjerlingP

SilversteinRA

ThonG

CaudyA

GrewalS

2002 Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity. Mol Cell Biol 22 2170 2181

5. BannisterAJ

ZegermanP

PartridgeJF

MiskaEA

ThomasJO

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

6. ZhangK

MoschK

FischleW

GrewalSI

2008 Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin. Nat Struct Mol Biol 15 381 388

7. SadaieM

IidaT

UranoT

NakayamaJ

2004 A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. EMBO J 23 3825 3835

8. GrewalSIS

KlarAJ

1997 A recombinationally repressed region between mat2 and mat3 loci shares homology to centromeric repeats and regulates directionality of mating-type switching in fission yeast. Genetics 146 1221 1238

9. VolpeTA

KidnerC

HallIM

TengG

GrewalSI

2002 Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297 1833 1837

10. CamHP

SugiyamaT

ChenES

ChenX

FitzGeraldPC

2005 Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome. Nat Genet 37 809 819

11. HallIM

ShankaranarayanaGD

NomaK

AyoubN

CohenA

2002 Establishment of a heterochromatin domain. Science 297 2232 2236

12. JiaS

NomaK

GrewalSIS

2004 RNAi-independent heterochromatin nucleation by the stress-activated ATF1/CREB family proteins. Science 304 1971 1976

13. KimHS

ChoiES

ShinJA

JangYK

ParkSD

2004 Regulation of Swi6/HP1-dependent heterochromatin assembly by cooperation of components of the mitogen-activated protein kinase pathway and a histone deacetylase Clr6. J Biol Chem 279 42850 42859

14. YamadaT

FischleW

SugiyamaT

AllisD

GrewalSIS

2005 The nucleation and maintenance of heterochromatin by a histone deacetylase in fission yeast. Mol Cell 20 173 185

15. ThonG

CohenA

KlarAJ

1994 Three additional linkage groups that repress transcription and meiotic recombination in the mating-type region of Schizosaccharomyces pombe. Genetics 138 29 38

16. ThonG

BjerlingKP

NielsenIS

1999 Localization and properties of a silencing element near the mat3-M mating-type cassette of Schizosaccharomyces pombe. Genetics 151 945 963

17. ThonG

HansenKR

AltesSP

SidhuD

SinghG

2005 The Clr7 and Clr8 directionality factors and the Pcu4 cullin mediate heterochromatin formation in the fission yeast Schizosaccharomyces pombe. Genetics 171 1583 1595

18. HansenKR

BurnsG

MataJ

VolpeTA

MartienssenRA

2005 Global effects on gene expression in fission yeast by silencing and RNA interference machineries. Mol Cell Biol 25 590 601

19. MataJ

LyneR

BurnsG

BählerJ

2002 The transcriptional program of meiosis and sporulation in fission yeast. Nat Genet 32 143 147

20. IshiiK

OgiyamaY

ChikashigeY

SoejimaS

MasudaF

2008 Heterochromatin integrity affects chromosome reorganization after centromere dysfunction. Science 321 1088 1091

21. AllshireRC

NimmoER

EkwallK

JaverzatJ

CranstonG

1995 Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. Genes Dev 9 218 233

22. ThonG

Verhein-HansenJ

2000 Four chromo-domain proteins of Schizosaccharomyces pombe differentially repress transcription at various chromosomal locations. Genetics 155 551 568

23. GrewalSIS

KlarAJ

1996 Chromosomal inheritance of epigenetic states in fission yeast during mitosis and meiosis. Cell 86 95 101

24. ThonG

FriisT

1997 Epigenetic inheritance of transcriptional silencing and switching competence in fission yeast. Genetics 145 685 696

25. AyoubN

NomaK

IsaacS

KahanT

GrewalSI

2003 A novel jmjC domain protein modulates heterochromatization in fission yeast. Mol Cell Biol 23 4356 4370

26. AyoubN

GoldschmidtI

LyakhovetskyR

CohenA

2000 A fission yeast repression element cooperates with centromere-like sequences and defines a mat silent domain boundary. Genetics 156 983 994

27. SugiyamaT

CamH

VerdelA

MoazedD

GrewalSI

2005 RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production. Proc Natl Acad Sci U S A 102 152 157

28. MotamediMR

HongEJ

LiX

GerberS

DenisonC

2008 HP1 proteins form distinct complexes and mediate heterochromatic gene silencing by nonoverlapping mechanisms. Mol Cell 32 778 790

29. SadaieM

KawaguchiR

OhtaniY

ArisakaF

TanakaK

2008 Balance between distinct HP1 family proteins controls heterochromatin assembly in fission yeast. Mol Cell Biol 28 6973 6988

30. FischerT

CuiB

DhakshnamoorthyJ

ZhouM

RubinC

2009 Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast. Proc Natl Acad Sci U S A 106 8998 9003

31. WirénM

SilversteinRA

SinhaI

WalfridssonJ

LeeHM

2005 Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast. EMBO J 24 2906 18

32. SinhaI

WirénM

EkwallK

2006 Genome-wide patterns of histone modifications in fission yeast. Chromosome Res 14 95 105

33. EkwallK

2005 Genome-wide analysis of HDAC function. Trends Genet 21 608 615

34. ChenES

ZhangK

NicolasE

CamHP

ZofallM

2008 Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature 451 734 737

35. CzerminB

SchottaG

HülsmannBB

BrehmA

BeckerPB

2001 Physical and functional association of SU(VAR)3-9 and HDAC1 in Drosophila. EMBO Rep 2 915 919

36. ZhangCL

McKinseyTA

OlsonEN

2002 Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Mol Cell Biol 22 7302 7312

37. AparicioOM

GottschlingDE

1994 Overcoming telomeric silencing: a trans-activator competes to establish gene expression in a cell cycle-dependent way. Genes Dev 8 1133 1146

38. XuEY

ZawadzkiKA

BroachJR

2006 Single-cell observations reveal intermediate transcriptional silencing states. Mol Cell 23 219 229

39. MartienssenRA

ZaratieguiM

GotoDB

2005 RNA interference and heterochromatin in the fission yeast Schizosaccharomyces pombe. Trends Genet 8 450 456

40. KanohJ

WatanabeY

OhsugiM

LinoY

YamamotoM

1996 Schizosaccharomyces pombe gad7+ encodes a phosphoprotein with a bZIP domain, which is required for proper G1 arrest and gene expression under nitrogen starvation. Genes Cells 1 391 408

41. KonN

KrawchukMD

WarrenBG

SmithGR

WahlsWP

1997 Transcription factor Mts1/Mts2 (Atf1/Pcr1, Gad7/Pcr1) activates the M26 meiotic recombination hotspot in Schizosaccharomyces pombe. Proc Natl Acad Sci U S A 94 13765 13770

42. LeemY

RipmasterTL

KellyFD

EbinaH

HeincelmanME

2008 Retrotransposon Tf1 is targeted to pol II promoters by transcription activators. Mol Cell 30 98 107

43. DeshpandeGP

HaylesJ

HoeKL

KimDU

ParkHO

2009 Screening a genome-wide S. pombe deletion library identifies novel genes and pathways involved in genome stability maintenance. DNA Repair (Amst) 8 672 679

44. NicolasE

YamadaT

CamHP

FitzgeraldPC

KobayashiR

2007 Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection. Nat Struct Mol Biol 14 372 380

45. WrightPE

DysonHJ

2009 Linking folding and binding. Curr Opin Struct Biol 19 31 38

46. MészárosB

TompaP

SimonI

DosztányiZ

2007 Molecular principles of the interactions of disordered proteins. J Mol Biol 372 549 561

47. BorkP

1993 Hundreds of ankyrin-like repeats in functionally diverse proteins: mobile modules that cross phyla horizontally? Proteins 17 363 374

48. BarrickD

FerreiroDU

KomivesEA

2008 Folding landscapes of ankyrin repeat proteins: experiments meet theory. Curr Opin Struct Biol 18 27 34

49. ZhangA

YeungPL

LiCW

TsaiSC

DinhGK

2004 Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. J Biol Chem 279 33799 33805

50. SedgwickSG

SmerdonSJ

1999 The ankyrin repeat: a diversity of interactions on a common structural framework. Trends Biochem Sci 24 311 316

51. LiJ

MahajanA

TsaiMD

2006 Ankyrin repeat: a unique motif mediating protein-protein interactions. Biochemistry 45 15168 15178

52. HayashiA

DingDQ

TsutsumiC

ChikashigeY

MasudaH

2009 Localization of gene products using a chromosomally tagged GFP-fusion library in the fission yeast Schizosaccharomyces pombe. Genes Cells 14 217 225

53. ThonG

KlarAJ

1992 The clr1 locus regulates the expression of the cryptic mating-type loci of fission yeast. Genetics 131 287 296

54. NielsenIS

NielsenO

MurrayJM

ThonG

2002 The fission yeast ubiquitin-conjugating enzymes UbcP3, Ubc15, and Rhp6 affect transcriptional silencing of the mating-type region. Eukaryot Cell 1 613 625

55. SatoM

DhutS

TodaT

2005 New drug-resistant cassettes for gene disruption and epitope tagging in Schizosaccharomyces pombe. Yeast 7 583 591

56. MorenoS

KlarAJS

NurseP

1991 Molecular genetic analysis of the fission yeast Schizosaccharomyces pombe. Method Enzymol 194 795 823

57. PetrieVJ

WuitschickJD

GivensCD

KosinskiAM

PartridgeJF

2005 RNA interference (RNAi)-dependent and RNAi-independent association of the Chp1 chromodomain protein with distinct heterochromatic loci in fission yeast. Mol Cell Biol 25 2331 2346

58. JonesJ

PrakashL

1990 Yeast Saccharomyces cerevisiae selectable markers in pUC18 polylinkers. Yeast 6 363 366

59. ChuaG

TaricaniL

StrangleW

YoungPG

2000 Insertional mutagenesis based on illegitimate recombination in Schizosaccharomyces pombe. Nucleic Acids Res 28 e53

60. HansenKR

IbarraPT

ThonG

2006 Evolutionary-conserved telomere-linked helicase genes of fission yeast are repressed by silencing factors, RNAi components and the telomere-binding protein Taz1. Nucleic Acids Res 34 78 88

61. PartridgeJF

DeBeauchampJL

KosinskiAM

UlrichDL

HadlerMJ

2007 Functional separation of the requirements for establishment and maintenance of centromeric heterochromatin. Mol Cell 26 593 602

62. LyneR

BurnsG

MataJ

PenkettCJ

RusticiG

2003 Whole-genome microarrays of fission yeast: characteristics, accuracy, reproducibility, and processing of array data. BMC Genomics 4 27

63. AltschulSF

GishW

MillerW

MyersEW

LipmanDJ

1990 Basic local alignment search tool. J Mol Biol 215 403 410

64. De CastroE

SigristCJ

GattikerA

BulliardV

Langendijk-GenevauxPS

2006 ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins. Nucleic Acids Res 34 Web Server issue W362 365

65. MataJ

BählerJ

2006 Global roles of Ste11p, cell type, and pheromone in the control of gene expression during early sexual differentiation in fission yeast. Proc Natl Acad Sci U S A 103 15517 15522

66. KupferDM

DrabenstotSD

BuchananKL

LaiH

ZhuH

2004 Introns and splicing elements of five diverse fungi. Eukaryot Cell 3 1088 1100

67. CaspariT

1997 Onset of gluconate-H+ symport in Schizosaccharomyces pombe is regulated by the kinase Wis1 and Pka1, and requires the gti+ gene product. J Cell Science 110 2599 2608

68. HarigayaY

YamamotoM

2007 Molecular mechanisms underlying the mitosis-meiosis decision. Chromosome Res 15 523 537

69. HeilandS

RadonovicN

HoferM

WinderrickxJ

LichtenbergH

2000 Multiple Hexose transporters of Schizosaccharomyces pombe. J Bacteriol 182 2153 2162

70. MataJ

BählerJ

2006 Global roles of Ste11p, cell type, and pheromone in the control of gene expression during early sexual meiosis differentiation in fission yeast. Proc Natl Acad Sci U S A 103 15517 15522

71. Xue-FranzénY

KjærulffS

HolmbergC

WrightA

NielsenO

2006 Genomewide identification of pheromone-targeted transcription in fission yeast. BMC Genomics 7 1 18

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