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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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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