Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV


Autoři: Nenavath Gopal Naik aff001;  Thomas Hong Nguyen aff001;  Lauren Roberts aff001;  Luke Todd Fischer aff001;  Katherine Glickman aff001;  Gavin Golas aff001;  Bernadett Papp aff001;  Zsolt Toth aff001
Působiště autorů: Department of Oral Biology, University of Florida College of Dentistry, 1395 Center Drive, Gainesville, FL, United States of America aff001;  UF Genetics Institute, Gainesville, FL, United States of America aff002;  UF Health Cancer Center, Gainesville, FL, United States of America aff003;  UF Informatics Institute, Gainesville, FL, United States of America aff004
Vyšlo v časopise: Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV. PLoS Pathog 16(1): e1008268. doi:10.1371/journal.ppat.1008268
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1008268

Souhrn

Establishment of viral latency is not only essential for lifelong Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, but it is also a prerequisite of viral tumorigenesis. The latent viral DNA has a complex chromatin structure, which is established in a stepwise manner regulated by host epigenetic factors during de novo infection. However, despite the importance of viral latency in KSHV pathogenesis, we still have limited information about the repertoire of epigenetic factors that are critical for the establishment and maintenance of KSHV latency. Therefore, the goal of this study was to identify host epigenetic factors that suppress lytic KSHV genes during primary viral infection, which would indicate their role in latency establishment. We performed an siRNA screen targeting 392 host epigenetic factors during primary infection and analyzed which ones affect the expression of the viral replication and transcription activator (RTA) and/or the latency-associated nuclear antigen (LANA), which are viral genes essential for lytic replication and latency, respectively. As a result, we identified the Nucleosome Remodeling and Deacetylase (NuRD) complex, Tip60 and Tip60-associated co-repressors, and the histone demethylase KDM2B as repressors of KSHV lytic genes during both de novo infection and the maintenance of viral latency. Furthermore, we showed that KDM2B rapidly binds to the incoming viral DNA as early as 8 hpi, and can limit the enrichment of activating histone marks on the RTA promoter favoring the downregulation of RTA expression even prior to the polycomb proteins-regulated heterochromatin establishment on the viral genome. Strikingly, KDM2B can also suppress viral gene expression and replication during lytic infection of primary gingival epithelial cells, revealing that KDM2B can act as a host restriction factor of the lytic cycle of KSHV during both latent and lytic infections in multiple different cell types.

Klíčová slova:

Epigenetics – Gene expression – Histones – Kaposi's sarcoma-associated herpesvirus – Small interfering RNAs – Viral gene expression – Viral persistence and latency – Virus effects on host gene expression


Zdroje

1. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869. doi: 10.1126/science.7997879 7997879

2. Dittmer DP, Damania B (2013) Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)—an update. Current opinion in virology 3: 238–244. doi: 10.1016/j.coviro.2013.05.012 23769237

3. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191. doi: 10.1056/NEJM199505043321802 7700311

4. Toth Z, Brulois K, Jung JU (2013) The chromatin landscape of Kaposi's sarcoma-associated herpesvirus. Viruses 5: 1346–1373. doi: 10.3390/v5051346 23698402

5. Tempera I, Lieberman PM (2010) Chromatin organization of gammaherpesvirus latent genomes. Biochim Biophys Acta 1799: 236–245. doi: 10.1016/j.bbagrm.2009.10.004 19853673

6. Toth Z, Maglinte DT, Lee SH, Lee HR, Wong LY, et al. (2010) Epigenetic analysis of KSHV latent and lytic genomes. PLoS Pathog 6: e1001013. doi: 10.1371/journal.ppat.1001013 20661424

7. Gunther T, Grundhoff A (2010) The epigenetic landscape of latent Kaposi sarcoma-associated herpesvirus genomes. PLoS Pathog 6: e1000935. doi: 10.1371/journal.ppat.1000935 20532208

8. Chen J, Ueda K, Sakakibara S, Okuno T, Parravicini C, et al. (2001) Activation of latent Kaposi's sarcoma-associated herpesvirus by demethylation of the promoter of the lytic transactivator. Proc Natl Acad Sci U S A 98: 4119–4124. doi: 10.1073/pnas.051004198 11274437

9. Hopcraft SE, Pattenden SG, James LI, Frye S, Dittmer DP, et al. (2018) Chromatin remodeling controls Kaposi's sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog 14: e1007267. doi: 10.1371/journal.ppat.1007267 30212584

10. Lu F, Zhou J, Wiedmer A, Madden K, Yuan Y, et al. (2003) Chromatin remodeling of the Kaposi's sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency. J Virol 77: 11425–11435. doi: 10.1128/JVI.77.21.11425-11435.2003 14557628

11. Li Q, He M, Zhou F, Ye F, Gao SJ (2014) Activation of Kaposi's sarcoma-associated herpesvirus (KSHV) by inhibitors of class III histone deacetylases: identification of sirtuin 1 as a regulator of the KSHV life cycle. J Virol 88: 6355–6367. doi: 10.1128/JVI.00219-14 24672028

12. Hu M, Armstrong N, Seto E, Li W, Zhu F, et al. (2019) Sirtuin 6 Attenuates Kaposi's Sarcoma-Associated Herpesvirus Reactivation by Suppressing Ori-Lyt Activity and Expression of RTA. J Virol 93.

13. Shin HJ, DeCotiis J, Giron M, Palmeri D, Lukac DM (2014) Histone deacetylase classes I and II regulate Kaposi's sarcoma-associated herpesvirus reactivation. J Virol 88: 1281–1292. doi: 10.1128/JVI.02665-13 24227836

14. Kang H, Wiedmer A, Yuan Y, Robertson E, Lieberman PM (2011) Coordination of KSHV latent and lytic gene control by CTCF-cohesin mediated chromosome conformation. PLoS Pathog 7: e1002140. doi: 10.1371/journal.ppat.1002140 21876668

15. Campbell M, Watanabe T, Nakano K, Davis RR, Lyu Y, et al. (2018) KSHV episomes reveal dynamic chromatin loop formation with domain-specific gene regulation. Nature communications 9: 49. doi: 10.1038/s41467-017-02089-9 29302027

16. Toth Z, Brulois KF, Wong LY, Lee HR, Chung B, et al. (2012) Negative elongation factor-mediated suppression of RNA polymerase II elongation of Kaposi's sarcoma-associated herpesvirus lytic gene expression. J Virol 86: 9696–9707. doi: 10.1128/JVI.01012-12 22740393

17. Aneja KK, Yuan Y (2017) Reactivation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus: An Update. Frontiers in microbiology 8: 613. doi: 10.3389/fmicb.2017.00613 28473805

18. Sun R, Lin SF, Gradoville L, Yuan Y, Zhu F, et al. (1998) A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 95: 10866–10871. doi: 10.1073/pnas.95.18.10866 9724796

19. Papp B, Motlagh N, Smindak RJ, Jin Jang S, Sharma A, et al. (2019) Genome-Wide Identification of Direct RTA Targets Reveals Key Host Factors for Kaposi's Sarcoma-Associated Herpesvirus Lytic Reactivation. J Virol 93.

20. Kim KY, Huerta SB, Izumiya C, Wang DH, Martinez A, et al. (2013) Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen regulates the KSHV epigenome by association with the histone demethylase KDM3A. J Virol 87: 6782–6793. doi: 10.1128/JVI.00011-13 23576503

21. Rossetto CC, Pari G (2012) KSHV PAN RNA associates with demethylases UTX and JMJD3 to activate lytic replication through a physical interaction with the virus genome. PLoS Pathog 8: e1002680. doi: 10.1371/journal.ppat.1002680 22589717

22. Chang PC, Fitzgerald LD, Hsia DA, Izumiya Y, Wu CY, et al. (2011) Histone demethylase JMJD2A regulates Kaposi's sarcoma-associated herpesvirus replication and is targeted by a viral transcriptional factor. J Virol 85: 3283–3293. doi: 10.1128/JVI.02485-10 21228229

23. Toth Z, Brulois K, Lee HR, Izumiya Y, Tepper C, et al. (2013) Biphasic Euchromatin-to-Heterochromatin Transition on the KSHV Genome Following De Novo Infection. PLoS Pathog 9: e1003813. doi: 10.1371/journal.ppat.1003813 24367262

24. Gunther T, Schreiner S, Dobner T, Tessmer U, Grundhoff A (2014) Influence of ND10 components on epigenetic determinants of early KSHV latency establishment. PLoS Pathog 10: e1004274. doi: 10.1371/journal.ppat.1004274 25033267

25. Toth Z, Papp B, Brulois K, Choi YJ, Gao SJ, et al. (2016) LANA-Mediated Recruitment of Host Polycomb Repressive Complexes onto the KSHV Genome during De Novo Infection. PLoS Pathog 12: e1005878. doi: 10.1371/journal.ppat.1005878 27606464

26. Krishnan HH, Naranatt PP, Smith MS, Zeng L, Bloomer C, et al. (2004) Concurrent expression of latent and a limited number of lytic genes with immune modulation and antiapoptotic function by Kaposi's sarcoma-associated herpesvirus early during infection of primary endothelial and fibroblast cells and subsequent decline of lytic gene expression. J Virol 78: 3601–3620. doi: 10.1128/JVI.78.7.3601-3620.2004 15016882

27. Toth Z, Smindak RJ, Papp B (2017) Inhibition of the lytic cycle of Kaposi's sarcoma-associated herpesvirus by cohesin factors following de novo infection. Virology 512: 25–33. doi: 10.1016/j.virol.2017.09.001 28898712

28. Duus KM, Lentchitsky V, Wagenaar T, Grose C, Webster-Cyriaque J (2004) Wild-type Kaposi's sarcoma-associated herpesvirus isolated from the oropharynx of immune-competent individuals has tropism for cultured oral epithelial cells. J Virol 78: 4074–4084. doi: 10.1128/JVI.78.8.4074-4084.2004 15047824

29. Brulois KF, Chang H, Lee AS, Ensser A, Wong LY, et al. (2012) Construction and manipulation of a new Kaposi's sarcoma-associated herpesvirus bacterial artificial chromosome clone. J Virol 86: 9708–9720. doi: 10.1128/JVI.01019-12 22740391

30. Torchy MP, Hamiche A, Klaholz BP (2015) Structure and function insights into the NuRD chromatin remodeling complex. Cellular and molecular life sciences: CMLS 72: 2491–2507. doi: 10.1007/s00018-015-1880-8 25796366

31. Sapountzi V, Logan IR, Robson CN (2006) Cellular functions of TIP60. The international journal of biochemistry & cell biology 38: 1496–1509.

32. Kang JY, Kim JY, Kim KB, Park JW, Cho H, et al. (2018) KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 32: 5737–5750.

33. Janzer A, Stamm K, Becker A, Zimmer A, Buettner R, et al. (2012) The H3K4me3 histone demethylase Fbxl10 is a regulator of chemokine expression, cellular morphology, and the metabolome of fibroblasts. J Biol Chem 287: 30984–30992. doi: 10.1074/jbc.M112.341040 22825849

34. He J, Nguyen AT, Zhang Y (2011) KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood 117: 3869–3880. doi: 10.1182/blood-2010-10-312736 21310926

35. Wu X, Johansen JV, Helin K (2013) Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Molecular cell 49: 1134–1146. doi: 10.1016/j.molcel.2013.01.016 23395003

36. Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, et al. (2012) KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. eLife 1: e00205. doi: 10.7554/eLife.00205 23256043

37. Baymaz HI, Fournier A, Laget S, Ji Z, Jansen PW, et al. (2014) MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domain. Proteomics 14: 2179–2189. doi: 10.1002/pmic.201400013 24634419

38. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, et al. (2010) Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465: 243–247. doi: 10.1038/nature08966 20436459

39. Lai A, Kennedy BK, Barbie DA, Bertos NR, Yang XJ, et al. (2001) RBP1 recruits the mSIN3-histone deacetylase complex to the pocket of retinoblastoma tumor suppressor family proteins found in limited discrete regions of the nucleus at growth arrest. Mol Cell Biol 21: 2918–2932. doi: 10.1128/MCB.21.8.2918-2932.2001 11283269

40. Stedman W, Deng Z, Lu F, Lieberman PM (2004) ORC, MCM, and histone hyperacetylation at the Kaposi's sarcoma-associated herpesvirus latent replication origin. J Virol 78: 12566–12575. doi: 10.1128/JVI.78.22.12566-12575.2004 15507644

41. Chen HS, Wikramasinghe P, Showe L, Lieberman PM (2012) Cohesins repress Kaposi's sarcoma-associated herpesvirus immediate early gene transcription during latency. J Virol 86: 9454–9464. doi: 10.1128/JVI.00787-12 22740398

42. Li DJ, Verma D, Mosbruger T, Swaminathan S (2014) CTCF and Rad21 act as host cell restriction factors for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication by modulating viral gene transcription. PLoS Pathog 10: e1003880. doi: 10.1371/journal.ppat.1003880 24415941

43. Chang H, Dittmer DP, Shin YC, Hong Y, Jung JU (2005) Role of Notch signal transduction in Kaposi's sarcoma-associated herpesvirus gene expression. J Virol 79: 14371–14382. doi: 10.1128/JVI.79.22.14371-14382.2005 16254371

44. Ballestas ME, Chatis PA, Kaye KM (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284: 641–644. doi: 10.1126/science.284.5414.641 10213686

45. Vargas-Ayala RC, Jay A, Manara F, Maroui MA, Hernandez-Vargas H, et al. (2019) Interplay between the Epigenetic Enzyme Lysine (K)-Specific Demethylase 2B and Epstein-Barr Virus Infection. J Virol 93.

46. Isshiki Y, Nakajima-Takagi Y, Oshima M, Aoyama K, Rizk M, et al. (2019) KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis. Blood advances 3: 2537–2549. doi: 10.1182/bloodadvances.2018028522 31471323

47. Ma G, Chen L, Luo J, Wang B, Wang C, et al. (2018) Histone acetyl transferase TIP60 inhibits the replication of influenza a virus by activation the TBK1-IRF3 pathway. Virology journal 15: 172. doi: 10.1186/s12985-018-1079-3 30409205

48. Yasunaga A, Hanna SL, Li J, Cho H, Rose PP, et al. (2014) Genome-wide RNAi screen identifies broadly-acting host factors that inhibit arbovirus infection. PLoS Pathog 10: e1003914. doi: 10.1371/journal.ppat.1003914 24550726

49. Terhune SS, Moorman NJ, Cristea IM, Savaryn JP, Cuevas-Bennett C, et al. (2010) Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA. PLoS Pathog 6: e1000965. doi: 10.1371/journal.ppat.1000965 20585571

50. Jha S, Vande Pol S, Banerjee NS, Dutta AB, Chow LT, et al. (2010) Destabilization of TIP60 by human papillomavirus E6 results in attenuation of TIP60-dependent transcriptional regulation and apoptotic pathway. Molecular cell 38: 700–711. doi: 10.1016/j.molcel.2010.05.020 20542002

51. Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, et al. (1999) The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. The EMBO journal 18: 2449–2458. doi: 10.1093/emboj/18.9.2449 10228159

52. Basta J, Rauchman M (2015) The nucleosome remodeling and deacetylase complex in development and disease. Translational research: the journal of laboratory and clinical medicine 165: 36–47.

53. Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G (1996) Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Virology 216: 357–366. doi: 10.1006/viro.1996.0071 8607265

54. Kimura A, Horikoshi M (1998) Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes to cells: devoted to molecular & cellular mechanisms 3: 789–800.

55. Sun XJ, Man N, Tan Y, Nimer SD, Wang L (2015) The Role of Histone Acetyltransferases in Normal and Malignant Hematopoiesis. Frontiers in oncology 5: 108. doi: 10.3389/fonc.2015.00108 26075180

56. Sun Y, Jiang X, Price BD (2010) Tip60: connecting chromatin to DNA damage signaling. Cell Cycle 9: 930–936. doi: 10.4161/cc.9.5.10931 20160506

57. Li B, Samanta A, Song X, Iacono KT, Bembas K, et al. (2007) FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci U S A 104: 4571–4576. doi: 10.1073/pnas.0700298104 17360565

58. Nordentoft I, Jorgensen P (2003) The acetyltransferase 60 kDa trans-acting regulatory protein of HIV type 1-interacting protein (Tip60) interacts with the translocation E26 transforming-specific leukaemia gene (TEL) and functions as a transcriptional co-repressor. The Biochemical journal 374: 165–173. doi: 10.1042/BJ20030087 12737628

59. Grezy A, Chevillard-Briet M, Trouche D, Escaffit F (2016) Control of genetic stability by a new heterochromatin compaction pathway involving the Tip60 histone acetyltransferase. Molecular biology of the cell 27: 599–607. doi: 10.1091/mbc.E15-05-0316 26700317

60. Shamay M, Liu J, Li R, Liao G, Shen L, et al. (2012) A protein array screen for Kaposi's sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening. J Virol 86: 5179–5191. doi: 10.1128/JVI.00169-12 22379092

61. Simpson S, Fiches G, Jean MJ, Dieringer M, McGuinness J, et al. (2018) Inhibition of Tip60 Reduces Lytic and Latent Gene Expression of Kaposi's Sarcoma-Associated Herpes Virus (KSHV) and Proliferation of KSHV-Infected Tumor Cells. Frontiers in microbiology 9: 788. doi: 10.3389/fmicb.2018.00788 29740418

62. Shahbazian MD, Grunstein M (2007) Functions of site-specific histone acetylation and deacetylation. Annual review of biochemistry 76: 75–100. doi: 10.1146/annurev.biochem.76.052705.162114 17362198

63. Strahan RC, McDowell-Sargent M, Uppal T, Purushothaman P, Verma SC (2017) KSHV encoded ORF59 modulates histone arginine methylation of the viral genome to promote viral reactivation. PLoS Pathog 13: e1006482. doi: 10.1371/journal.ppat.1006482 28678843

64. Schmitges FW, Prusty AB, Faty M, Stutzer A, Lingaraju GM, et al. (2011) Histone methylation by PRC2 is inhibited by active chromatin marks. Molecular cell 42: 330–341. doi: 10.1016/j.molcel.2011.03.025 21549310

65. Nguyen AT, Zhang Y (2011) The diverse functions of Dot1 and H3K79 methylation. Genes & development 25: 1345–1358.

66. Gunther T, Frohlich J, Herrde C, Ohno S, Burkhardt L, et al. (2019) A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment. PLoS Pathog 15: e1007838. doi: 10.1371/journal.ppat.1007838 31671162

67. Laugesen A, Hojfeldt JW, Helin K (2019) Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation. Molecular cell 74: 8–18. doi: 10.1016/j.molcel.2019.03.011 30951652

68. Yu M, Mazor T, Huang H, Huang HT, Kathrein KL, et al. (2012) Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Molecular cell 45: 330–343. doi: 10.1016/j.molcel.2011.11.032 22325351

69. Boccuni P, MacGrogan D, Scandura JM, Nimer SD (2003) The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6). J Biol Chem 278: 15412–15420. doi: 10.1074/jbc.M300592200 12588862

70. Reynolds N, Salmon-Divon M, Dvinge H, Hynes-Allen A, Balasooriya G, et al. (2012) NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression. The EMBO journal 31: 593–605. doi: 10.1038/emboj.2011.431 22139358

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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