Histone Deacetylases Play a Major Role in the Transcriptional Regulation of the Life Cycle

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The apparent paucity of molecular factors of transcriptional control in the genomes of Plasmodium parasites raises many questions about the mechanisms of life cycle regulation in these malaria parasites. Epigenetic regulation has been suggested to play a major role in the stage specific gene expression during the Plasmodium life cycle. To address some of these questions, we analyzed global transcriptional responses of Plasmodium falciparum to a potent inhibitor of histone deacetylase activities (HDAC). The inhibitor apicidin induced profound transcriptional changes in multiple stages of the P. falciparum intraerythrocytic developmental cycle (IDC) that were characterized by rapid activation and repression of a large percentage of the genome. A major component of this response was induction of genes that are otherwise suppressed during that particular stage of the IDC or specific for the exo-erythrocytic stages. In the schizont stage, apicidin induced hyperacetylation of histone lysine residues H3K9, H4K8 and the tetra-acetyl H4 (H4Ac4) and demethylation of H3K4me3. Interestingly, we observed overlapping patterns of chromosomal distributions between H4K8Ac and H3K4me3 and between H3K9Ac and H4Ac4. There was a significant but partial association between the apicidin-induced gene expression and histone modifications, which included a number of stage specific transcription factors. Taken together, inhibition of HDAC activities leads to dramatic de-regulation of the IDC transcriptional cascade, which is a result of both disruption of histone modifications and up-regulation of stage specific transcription factors. These findings suggest an important role of histone modification and chromatin remodeling in transcriptional regulation of the Plasmodium life cycle. This also emphasizes the potential of P. falciparum HDACs as drug targets for malaria chemotherapy.

Vyšlo v časopise: Histone Deacetylases Play a Major Role in the Transcriptional Regulation of the Life Cycle. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000737
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000737

Souhrn

Zdroje

1. BozdechZ

LlinasM

PulliamBL

WongED

ZhuJ

2003 The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol 1 e5 doi:10.1371/journal.pbio.0000005

2. Le RochKG

ZhouY

BlairPL

GraingerM

MochJK

2003 Discovery of gene function by expression profiling of the malaria parasite life cycle. Science 301 1503 1508

3. BozdechZ

MokS

HuG

ImwongM

JaideeA

2008 The transcriptome of Plasmodium vivax reveals divergence and diversity of transcriptional regulation in malaria parasites. Proc Natl Acad Sci U S A 105 16290 16295

4. KouzaridesT

2007 Chromatin modifications and their function. Cell 128 693 705

5. LiJ

LinQ

WangW

WadeP

WongJ

2002 Specific targeting and constitutive association of histone deacetylase complexes during transcriptional repression. Genes Dev 16 687 692

6. BryantGO

PtashneM

2003 Independent recruitment in vivo by Gal4 of two complexes required for transcription. Mol Cell 11 1301 1309

7. VogelauerM

WuJ

SukaN

GrunsteinM

2000 Global histone acetylation and deacetylation in yeast. Nature 408 495 498

8. Katan-KhaykovichY

StruhlK

2002 Dynamics of global histone acetylation and deacetylation in vivo: rapid restoration of normal histone acetylation status upon removal of activators and repressors. Genes Dev 16 743 752

9. YangXJ

SetoE

2008 The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9 206 218

10. GasserSM

CockellMM

2001 The molecular biology of the SIR proteins. Gene 279 1 16

11. JoshiMB

LinDT

ChiangPH

GoldmanND

FujiokaH

1999 Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum. Mol Biochem Parasitol 99 11 19

12. Freitas-JuniorLH

Hernandez-RivasR

RalphSA

Montiel-CondadoD

Ruvalcaba-SalazarOK

2005 Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121 25 36

13. GardnerMJ

HallN

FungE

WhiteO

BerrimanM

2002 Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419 498 511

14. MottetD

CastronovoV

2008 Histone deacetylases: target enzymes for cancer therapy. Clin Exp Metastasis 25 183 189

15. BougdourA

MaubonD

BaldacciP

OrtetP

BastienO

2009 Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites. J Exp Med 206 953 966

16. Darkin-RattraySJ

GurnettAM

MyersRW

DulskiPM

CrumleyTM

1996 Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci U S A 93 13143 13147

17. PatelV

MazitschekR

ColemanB

NguyenC

UrgaonkarS

2009 Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum. J Med Chem 52 2185 2187

18. HuG

LlinasM

LiJ

PreiserPR

BozdechZ

2007 Selection of long oligonucleotides for gene expression microarrays using weighted rank-sum strategy. BMC Bioinformatics 8 350

19. GunasekeraAM

MyrickA

Le RochK

WinzelerE

WirthDF

2007 Plasmodium falciparum: genome wide perturbations in transcript profiles among mixed stage cultures after chloroquine treatment. Exp Parasitol 117 87 92

20. GanesanK

PonmeeN

JiangL

FowbleJW

WhiteJ

2008 A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates. PLoS Pathog 4 e1000214 doi:10.1371/journal.ppat.1000214

21. CuiL

MiaoJ

FuruyaT

FanQ

LiX

2008 Histone acetyltransferase inhibitor anacardic acid causes changes in global gene expression during in vitro Plasmodium falciparum development. Eukaryot Cell 7 1200 1210

22. SilvestriniF

BozdechZ

LanfrancottiA

Di GiulioE

BultriniE

2005 Genome-wide identification of genes upregulated at the onset of gametocytogenesis in Plasmodium falciparum. Mol Biochem Parasitol 143 100 110

23. TempletonTJ

KaslowDC

1999 Identification of additional members define a Plasmodium falciparum gene superfamily which includes Pfs48/45 and Pfs230. Mol Biochem Parasitol 101 223 227

24. AlanoP

ReadD

BruceM

AikawaM

KaidoT

1995 COS cell expression cloning of Pfg377, a Plasmodium falciparum gametocyte antigen associated with osmiophilic bodies. Mol Biochem Parasitol 74 143 156

25. KappeSH

GardnerMJ

BrownSM

RossJ

MatuschewskiK

2001 Exploring the transcriptome of the malaria sporozoite stage. Proc Natl Acad Sci U S A 98 9895 9900

26. AndrewsKT

TranTN

LuckeAJ

KahnbergP

LeGT

2008 Potent antimalarial activity of histone deacetylase inhibitor analogues. Antimicrob Agents Chemother 52 1454 1461

27. CuiL

MiaoJ

FuruyaT

LiX

SuXZ

2007 PfGCN5-mediated histone H3 acetylation plays a key role in gene expression in Plasmodium falciparum. Eukaryot Cell 6 1219 1227

28. BarskiA

CuddapahS

CuiK

RohTY

SchonesDE

2007 High-resolution profiling of histone methylations in the human genome. Cell 129 823 837

29. MiaoJ

FanQ

CuiL

LiJ

2006 The malaria parasite Plasmodium falciparum histones: organization, expression, and acetylation. Gene 369 53 65

30. TusherVG

TibshiraniR

ChuG

2001 Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98 5116 5121

31. Salcedo-AmayaAM

van DrielMA

AlakoBT

TrelleMB

van den ElzenAM

2009 Dynamic histone H3 epigenome marking during the intraerythrocytic cycle of Plasmodium falciparum. Proc Natl Acad Sci U S A 106 9655 9660

32. CoppiA

Pinzon-OrtizC

HutterC

SinnisP

2005 The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion. J Exp Med 201 27 33

33. KurdistaniSK

TavazoieS

GrunsteinM

2004 Mapping global histone acetylation patterns to gene expression. Cell 117 721 733

34. BalajiS

BabuMM

IyerLM

AravindL

2005 Discovery of the principal specific transcription factors of Apicomplexa and their implication for the evolution of the AP2-integrase DNA binding domains. Nucleic Acids Res 33 3994 4006

35. De SilvaEK

GehrkeAR

OlszewskiK

LeonI

ChahalJS

2008 Specific DNA-binding by apicomplexan AP2 transcription factors. Proc Natl Acad Sci U S A 105 8393 8398

36. Perez-ToledoK

Rojas-MezaAP

Mancio-SilvaL

Hernandez-CuevasNA

DelgadilloDM

2009 Plasmodium falciparum heterochromatin protein 1 binds to tri-methylated histone 3 lysine 9 and is linked to mutually exclusive expression of var genes. Nucleic Acids Res 37 2596 2606

37. FlueckC

BartfaiR

VolzJ

NiederwieserI

Salcedo-AmayaAM

2009 Plasmodium falciparum heterochromatin protein 1 marks genomic loci linked to phenotypic variation of exported virulence factors. PLoS Pathog 5 e1000569 doi:10.1371/journal.ppat.1000569

38. CoulsonRM

HallN

OuzounisCA

2004 Comparative genomics of transcriptional control in the human malaria parasite Plasmodium falciparum. Genome Res 14 1548 1554

39. BernsteinBE

TongJK

SchreiberSL

2000 Genomewide studies of histone deacetylase function in yeast. Proc Natl Acad Sci U S A 97 13708 13713

40. GlaserKB

StaverMJ

WaringJF

StenderJ

UlrichRG

2003 Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2 151 163

41. XuWS

ParmigianiRB

MarksPA

2007 Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26 5541 5552

42. SmithAT

Tucker-SamarasSD

FairlambAH

SullivanWJJr

2005 MYST family histone acetyltransferases in the protozoan parasite Toxoplasma gondii. Eukaryot Cell 4 2057 2065

43. AgaliotiT

ChenG

ThanosD

2002 Deciphering the transcriptional histone acetylation code for a human gene. Cell 111 381 392

44. LupienM

EeckhouteJ

MeyerCA

WangQ

ZhangY

2008 FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132 958 970

45. WuLP

WangX

LiL

ZhaoY

LuS

2008 Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both CpG and H3K9 methylation on the promoter. Mol Cell Biol 28 3219 3235

46. MunshiA

ShafiG

AliyaN

JyothyA

2009 Histone modifications dictate specific biological readouts. J Genet Genomics 36 75 88

47. Lopez-RubioJJ

Mancio-SilvaL

ScherfA

2009 Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites. Cell Host Microbe 5 179 190

48. BergerSL

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

49. TarunAS

PengX

DumpitRF

OgataY

Silva-RiveraH

2008 A combined transcriptome and proteome survey of malaria parasite liver stages. Proc Natl Acad Sci U S A 105 305 310

50. YoungJA

FivelmanQL

BlairPL

de la VegaP

Le RochKG

2005 The Plasmodium falciparum sexual development transcriptome: a microarray analysis using ontology-based pattern identification. Mol Biochem Parasitol 143 67 79

51. BozdechZ

ZhuJ

JoachimiakMP

CohenFE

PulliamB

2003 Expression profiling of the schizont and trophozoite stages of Plasmodium falciparum with a long-oligonucleotide microarray. Genome Biol 4 R9

52. BohlanderSK

EspinosaR3rd

Le BeauMM

RowleyJD

DiazMO

1992 A method for the rapid sequence-independent amplification of microdissected chromosomal material. Genomics 13 1322 1324