CpG-Methylation Regulates a Class of Epstein-Barr Virus Promoters

English version České info

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian gene regulation. In general, cytosine-phosphatidyl-guanosine (CpG)-methylated promoters are transcriptionally repressed and nuclear proteins such as MECP2, MBD1, MBD2, and MBD4 bind CpG-methylated DNA and contribute to epigenetic silencing. Methylation of viral DNA also regulates gene expression of Epstein-Barr virus (EBV), which is a model of herpes virus latency. In latently infected human B cells, the viral DNA is CpG-methylated, the majority of viral genes is repressed and virus synthesis is therefore abrogated. EBV's BZLF1 encodes a transcription factor of the AP-1 family (Zta) and is the master gene to overcome viral gene repression. In a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. We identified novel DNA recognition motifs, termed meZRE (methyl-Zta-responsive element), which Zta selectively binds in order to ‘read’ DNA in a methylation- and sequence-dependent manner unlike any other known protein. Zta is a homodimer but its binding characteristics to meZREs suggest a sequential, non-palindromic and bipartite DNA recognition element, which confers superior DNA binding compared to CpG-free ZREs. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing.

Vyšlo v časopise: CpG-Methylation Regulates a Class of Epstein-Barr Virus Promoters. PLoS Pathog 6(9): e32767. doi:10.1371/journal.ppat.1001114
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001114

Souhrn

Zdroje

1. MaatoukDM

KellamLD

MannMR

LeiH

LiE

2006 DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development 133 3411 3418

2. MohnF

WeberM

RebhanM

RoloffTC

RichterJ

2008 Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 30 755 766

3. KallaM

SchmeinckA

BergbauerM

PichD

HammerschmidtW

2010 AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. Proc Natl Acad Sci U S A 107 850 855

4. KieffE

RickinsonAB

2007 Epstein-Barr virus and its replication.

KnipeDM

HowleyPM

GriffinDE

MartinMA

LambRA

RoizmanB

StrausSE

Fields Virology Philadelphia Lippincott - Williams & Wilkins 2603 2654

5. YoungLS

RickinsonAB

2004 Epstein-Barr virus: 40 years on. Nat Rev Cancer 4 757 768

6. TakadaK

ShimizuN

SakumaS

OnoY

1986 Transactivation of the latent Epstein-Barr virus (EBV) genome after transfection of the EBV DNA fragment. J Virol 57 1016 1022

7. CountrymanJ

JensonH

SeiblR

WolfH

MillerG

1987 Polymorphic proteins encoded within BZLF1 of defective and standard Epstein-Barr viruses disrupt latency. J Virol 61 3672 3679

8. SinclairAJ

2003 bZIP proteins of human gammaherpesviruses. J Gen Virol 84 1941 1949

9. FarrellPJ

RoweDT

RooneyCM

KouzaridesT

1989 Epstein-Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO J 8 127 132

10. Chevallier-GrecoA

ManetE

ChavrierP

MosnierC

DaillieJ

1986 Both Epstein-Barr virus (EBV)-encoded trans-acting factors, EB1 and EB2, are required to activate transcription from an EBV early promoter. Embo J 5 3243 3249

11. SchepersA

PichD

HammerschmidtW

1993 A transcription factor with homology to the AP-1 family links RNA transcription and DNA replication in the lytic cycle of Epstein-Barr virus. Embo J 12 3921 3929

12. FeederleR

KostM

BaumannM

JanzA

DrouetE

2000 The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J 19 3080 3089

13. BhendePM

SeamanWT

DelecluseHJ

KenneySC

2004 The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nat Genet 36 1099 1104

14. DickersonSJ

XingY

RobinsonAR

SeamanWT

GruffatH

2009 Methylation-dependent binding of the Epstein-Barr virus BZLF1 protein to viral promoters. PLoS Pathog 5 e1000356

15. KarlssonQH

SchelcherC

VerrallE

PetosaC

SinclairAJ

2008 Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein. PLoS Pathog 4 e1000005

16. SchaeferBC

StromingerJL

SpeckSH

1997 Host-cell-determined methylation of specific Epstein-Barr virus promoters regulates the choice between distinct viral latency programs. Mol Cell Biol 17 364 377

17. MinarovitsJ

2006 Epigenotypes of latent herpesvirus genomes. Curr Top Microbiol Immunol 310 61 80

18. DelecluseHJ

HilsendegenT

PichD

ZeidlerR

HammerschmidtW

1998 Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A 95 8245 8250

19. RothbauerU

ZolghadrK

MuyldermansS

SchepersA

CardosoMC

2008 A versatile nanotrap for biochemical and functional studies with fluorescent fusion proteins. Mol Cell Proteomics 7 282 289

20. BaerR

BankierAT

BigginMD

DeiningerPL

FarrellPJ

1984 DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 310 207 211

21. UrierG

BuissonM

ChambardP

SergeantA

1989 The Epstein-Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J 8 1447 1453

22. LiebermanPM

HardwickJM

SampleJ

HaywardGS

HaywardSD

1990 The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions. J Virol 64 1143 1155

23. HammerschmidtW

SugdenB

1988 Identification and characterization of oriLyt, a lytic origin of DNA replication of Epstein-Barr virus. Cell 55 427 433

24. FlemingtonE

SpeckSH

1990 Autoregulation of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol 64 1227 1232

25. PackhamG

EconomouA

RooneyCM

RoweDT

FarrellPJ

1990 Structure and function of the Epstein-Barr virus BZLF1 protein. J Virol 64 2110 2116

26. BhendePM

SeamanWT

DelecluseHJ

KenneySC

2005 BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. J Virol 79 7338 7348

27. KenneySC

Holley-GuthrieE

QuinlivanEB

GutschD

ZhangQ

1992 The cellular oncogene c-myb can interact synergistically with the Epstein-Barr virus BZLF1 transactivator in lymphoid cells. Mol Cell Biol 12 136 146

28. QuinlivanEB

Holley-GuthrieEA

NorrisM

GutschD

BachenheimerSL

1993 Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein-Barr virus early promoter, BMRF1. Nucleic Acids Res 21 1999 2007

29. RooneyCM

RoweDT

RagotT

FarrellPJ

1989 The spliced BZLF1 gene of Epstein-Barr virus (EBV) transactivates an early EBV promoter and induces the virus productive cycle. J Virol 63 3109 3116

30. GranatoM

FarinaA

GonnellaR

SantarelliR

FratiL

2006 Regulation of the expression of the Epstein-Barr virus early gene BFRF1. Virology 347 109 116

31. HungCH

LiuST

1999 Characterization of the Epstein-Barr virus BALF2 promoter. J Gen Virol 80 2747 2750

32. NakayamaS

MurataT

MurayamaK

YasuiY

SatoY

2009 Epstein-Barr Virus Polymerase Processivity Factor Enhances BALF2 Promoter Transcription as a Coactivator for the BZLF1 Immediate-Early Protein. J Biol Chem 284 21557 21568

33. FixmanED

HaywardGS

HaywardSD

1992 trans-acting requirements for replication of Epstein-Barr virus ori-Lyt. J Virol 66 5030 5039

34. GruffatH

BatisseJ

PichD

NeuhierlB

ManetE

2002 Epstein-Barr virus mRNA export factor EB2 is essential for production of infectious virus. J Virol 76 9635 9644

35. JothiR

CuddapahS

BarskiA

CuiK

ZhaoK

2008 Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 36 5221 5231

36. BaileyTL

WilliamsN

MislehC

LiWW

2006 MEME: discovering and analyzing DNA and protein sequence motifs. Nucleic Acids Res 34 W369 73

37. ValouevA

JohnsonDS

SundquistA

MedinaC

AntonE

2008 Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nat Methods 5 829 834

38. HeatherJ

FlowerK

IsaacS

SinclairAJ

2009 The Epstein-Barr virus lytic cycle activator Zta interacts with methylated ZRE in the promoter of host target gene egr1. J Gen Virol 90 1450 1454

39. KlugM

RehliM

2006 Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector. Epigenetics 1 127 130

40. BuissonM

ManetE

TrescolBM

GruffatH

DurandB

1989 The Epstein-Barr virus (EBV) early protein EB2 is a posttranscriptional activator expressed under the control of EBV transcription factors EB1 and R. J Virol 63 5276 5284

41. LiuQ

SummersWC

1992 Identification of the 12-O-tetradecanoylphorbol-13-acetate-responsive enhancer of the MS gene of the Epstein-Barr virus. J Biol Chem 267 12049 12054

42. KenneyS

Holley-GuthrieE

MarEC

SmithM

1989 The Epstein-Barr virus BMLF1 promoter contains an enhancer element that is responsive to the BZLF1 and BRLF1 transactivators. J Virol 63 3878 3883

43. RyderSP

RechtMI

WilliamsonJR

2008 Quantitative analysis of protein-RNA interactions by gel mobility shift. Methods Mol Biol 488 99 115

44. LehmanAM

EllwoodKB

MiddletonBE

CareyM

1998 Compensatory energetic relationships between upstream activators and the RNA polymerase II general transcription machinery. J Biol Chem 273 932 939

45. ChytilM

PetersonBR

ErlansonDA

VerdineGL

1998 The orientation of the AP-1 heterodimer on DNA strongly affects transcriptional potency. Proc Natl Acad Sci U S A 95 14076 14081

46. WilliamsJS

AndrisaniOM

1995 The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. Proc Natl Acad Sci U S A 92 3819 3823

47. WenW

IwakiriD

YamamotoK

MaruoS

KandaT

2007 Epstein-Barr virus BZLF1 gene, a switch from latency to lytic infection, is expressed as an immediate-early gene after primary infection of B lymphocytes. J Virol 81 1037 1042

48. AdamsonAL

KenneyS

1999 The Epstein-Barr virus BZLF1 protein interacts physically and functionally with the histone acetylase CREB-binding protein. J Virol 73 6551 6558

49. ZerbyD

ChenCJ

PoonE

LeeD

ShiekhattarR

1999 The amino-terminal C/H1 domain of CREB binding protein mediates zta transcriptional activation of latent Epstein-Barr virus. Mol Cell Biol 19 1617 1626

50. GuentherMG

LevineSS

BoyerLA

JaenischR

YoungRA

2007 A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130 77 88

51. MellorJ

DudekP

ClynesD

2008 A glimpse into the epigenetic landscape of gene regulation. Curr Opin Genet Dev 18 116 122

52. MikkelsenTS

KuM

JaffeDB

IssacB

LiebermanE

2007 Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448 553 560

53. PetosaC

MorandP

BaudinF

MoulinM

ArteroJB

2006 Structural basis of lytic cycle activation by the Epstein-Barr virus ZEBRA protein. Mol Cell 21 565 572

54. LeonardDA

KerppolaTK

1998 DNA bending determines Fos-Jun heterodimer orientation. Nat Struct Biol 5 877 881

55. Ramirez-CarrozziV

KerppolaT

2003 Asymmetric recognition of nonconsensus AP-1 sites by Fos-Jun and Jun-Jun influences transcriptional cooperativity with NFAT1. Mol Cell Biol 23 1737 1749

56. GloverJN

HarrisonSC

1995 Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA. Nature 373 257 261

57. GloecknerCJ

BoldtK

SchumacherA

RoepmanR

UeffingM

2007 A novel tandem affinity purification strategy for the efficient isolation and characterisation of native protein complexes. Proteomics 7 4228 4234

58. LiH

RuanJ

DurbinR

2008 Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res 18 1851 1858

59. BaileyTL

BodenM

BuskeFA

FrithM

GrantCE

2009 MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res 37 W202 8