Chromatin dynamics and the transcriptional competence of HSV-1 genomes during lytic infections

Autoři: MiYao Hu aff001;  Daniel P. Depledge aff003;  Esteban Flores Cortes aff002;  Judith Breuer aff003;  Luis M. Schang aff001
Působiště autorů: University of Alberta, Department of Biochemistry, Edmonton, AB, Canada aff001;  Cornell University, College of Veterinary Medicine, Baker institute for animal health, Ithaca, NY, United States of America aff002;  6401Division of Infection and Immunity, University College London, London, United Kingdom aff003
Vyšlo v časopise: Chromatin dynamics and the transcriptional competence of HSV-1 genomes during lytic infections. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008076
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008076


During latent infections with herpes simplex virus 1 (HSV-1), viral transcription is restricted and the genomes are mostly maintained in silenced chromatin, whereas in lytically infected cells all viral genes are transcribed and the genomes are dynamically chromatinized. Histones in the viral chromatin bear markers of silenced chromatin at early times in lytic infection or of active transcription at later times. The virion protein VP16 activates transcription of the immediate-early (IE) genes by recruiting transcription activators and chromatin remodelers to their promoters. Two IE proteins, ICP0 and ICP4 which modulate chromatin epigenetics, then activate transcription of early and late genes. Although chromatin is involved in the mechanism of activation of HSV- transcription, its precise role is not entirely understood. In the cellular genome, chromatin dynamics often modulate transcription competence whereas promoter-specific transcription factors determine transcription activity. Here, biophysical fractionation of serially digested HSV-1 chromatin followed by short-read deep sequencing indicates that nuclear HSV-1 DNA has different biophysical properties than protein-free or encapsidated HSV-1 DNA. The entire HSV-1 genomes in infected cells were equally accessible. The accessibility of transcribed or non-transcribed genes under any given condition did not differ, and each gene was entirely sampled in both the most and least accessible chromatin. However, HSV-1 genomes fractionated differently under conditions of generalized or restricted transcription. Approximately 1/3 of the HSV-1 DNA including fully sampled genes resolved to the most accessible chromatin when HSV-1 transcription was active, but such enrichment was reduced to only 3% under conditions of restricted HSV-1 transcription. Short sequences of restricted accessibility separated genes with different transcription levels. Chromatin dynamics thus provide a first level of regulation on HSV-1 transcription, dictating the transcriptional competency of the genomes during lytic infections, whereas the transcription of individual genes is then most likely activated by specific transcription factors. Moreover, genes transcribed to different levels are separated by short sequences with limited accessibility.

Klíčová slova:

DNA – DNA transcription – Functional genomics – Herpes simplex virus-1 – Histones – Chromatin – Sequence motif analysis – Transcriptional control


1. Deshmane SL, Fraser NW. During latency, herpes simplex virus type 1 DNA is associated with nucleosomes in a chromatin structure. J Virol. 1989;63(2):943–7. 2536115

2. Cliffe AR, Garber DA, Knipe DM. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol. 2009;83(16):8182–90. doi: 10.1128/JVI.00712-09 19515781

3. Wang QY, Zhou C, Johnson KE, Colgrove RC, Coen DM, Knipe DM. Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection. Proc Natl Acad Sci U S A. 2005;102(44):16055–9. doi: 10.1073/pnas.0505850102 16247011

4. Bloom DC, Giordani NV, Kwiatkowski DL. Epigenetic regulation of latent HSV-1 gene expression. Biochim Biophys Acta. 2010;1799(3–4):246–56. doi: 10.1016/j.bbagrm.2009.12.001 20045093

5. Lacasse JJ, Schang LM. During lytic infections, herpes simplex virus type 1 DNA is in complexes with the properties of unstable nucleosomes. J Virol. 2010;84(4):1920–33. doi: 10.1128/JVI.01934-09 20007274

6. Lacasse JJ, Schang LM. Herpes simplex virus 1 DNA is in unstable nucleosomes throughout the lytic infection cycle, and the instability of the nucleosomes is independent of DNA replication. J Virol. 2012;86(20):11287–300. doi: 10.1128/JVI.01468-12 22875975

7. Gibeault RL, Conn KL, Bildersheim MD, Schang LM. An Essential Viral Transcription Activator Modulates Chromatin Dynamics. PLoS Pathog. 2016;12(8):e1005842. doi: 10.1371/journal.ppat.1005842 27575707

8. Leinbach SS, Summers WC. The structure of herpes simplex virus type 1 DNA as probed by micrococcal nuclease digestion. J Gen Virol. 1980;51(Pt 1):45–59. doi: 10.1099/0022-1317-51-1-45 6257837

9. Mouttet ME, Guetard D, Bechet JM. Random cleavage of intranuclear herpes simplex virus DNA by micrococcal nuclease. FEBS Lett. 1979;100(1):107–9. doi: 10.1016/0014-5793(79)81141-2 220083

10. Lentine AF, Bachenheimer SL. Intracellular organization of herpes simplex virus type 1 DNA assayed by staphylococcal nuclease sensitivity. Virus Res. 1990;16(3):275–92. doi: 10.1016/0168-1702(90)90053-e 2168112

11. Kent JR, Zeng PY, Atanasiu D, Gardner J, Fraser NW, Berger SL. During lytic infection herpes simplex virus type 1 is associated with histones bearing modifications that correlate with active transcription. J Virol. 2004;78(18):10178–86. doi: 10.1128/JVI.78.18.10178-10186.2004 15331750

12. Kutluay SB, Triezenberg SJ. Regulation of histone deposition on the herpes simplex virus type 1 genome during lytic infection. J Virol. 2009;83(11):5835–45. doi: 10.1128/JVI.00219-09 19321615

13. Oh J, Sanders IF, Chen EZ, Li H, Tobias JW, Isett RB, et al. Genome wide nucleosome mapping for HSV-1 shows nucleosomes are deposited at preferred positions during lytic infection. PLoS One. 2015;10(2):e0117471. doi: 10.1371/journal.pone.0117471 25710170

14. Dembowski JA, DeLuca NA. Selective recruitment of nuclear factors to productively replicating herpes simplex virus genomes. PLoS Pathog. 2015;11(5):e1004939. doi: 10.1371/journal.ppat.1004939 26018390

15. Dembowski JA, DeLuca NA. Temporal Viral Genome-Protein Interactions Define Distinct Stages of Productive Herpesviral Infection. MBio. 2018;9(4).

16. Wysocka J, Herr W. The herpes simplex virus VP16-induced complex: the makings of a regulatory switch. Trends Biochem Sci. 2003;28(6):294–304. doi: 10.1016/S0968-0004(03)00088-4 12826401

17. O'Hare P, Goding CR. Herpes simplex virus regulatory elements and the immunoglobulin octamer domain bind a common factor and are both targets for virion transactivation. Cell. 1988;52(3):435–45. doi: 10.1016/s0092-8674(88)80036-9 2830987

18. Preston CM, Frame MC, Campbell ME. A complex formed between cell components and an HSV structural polypeptide binds to a viral immediate early gene regulatory DNA sequence. Cell. 1988;52(3):425–34. doi: 10.1016/s0092-8674(88)80035-7 2830986

19. Herrera FJ, Triezenberg SJ. VP16-dependent association of chromatin-modifying coactivators and underrepresentation of histones at immediate-early gene promoters during herpes simplex virus infection. J Virol. 2004;78(18):9689–96. doi: 10.1128/JVI.78.18.9689-9696.2004 15331701

20. Kristie TM, Liang Y, Vogel JL. Control of alpha-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activities. Biochim Biophys Acta. 2010;1799(3–4):257–65. doi: 10.1016/j.bbagrm.2009.08.003 19682612

21. Kristie TM, Roizman B. Host cell proteins bind to the cis-acting site required for virion-mediated induction of herpes simplex virus 1 alpha genes. Proc Natl Acad Sci U S A. 1987;84(1):71–5. doi: 10.1073/pnas.84.1.71 3025864

22. Wysocka J, Myers MP, Laherty CD, Eisenman RN, Herr W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 2003;17(7):896–911. doi: 10.1101/gad.252103 12670868

23. Hancock MH, Cliffe AR, Knipe DM, Smiley JR. Herpes simplex virus VP16, but not ICP0, is required to reduce histone occupancy and enhance histone acetylation on viral genomes in U2OS osteosarcoma cells. J Virol. 2010;84(3):1366–75. doi: 10.1128/JVI.01727-09 19939931

24. Peng H, Nogueira ML, Vogel JL, Kristie TM. Transcriptional coactivator HCF-1 couples the histone chaperone Asf1b to HSV-1 DNA replication components. Proc Natl Acad Sci U S A. 2010;107(6):2461–6. doi: 10.1073/pnas.0911128107 20133788

25. Tumbar T, Sudlow G, Belmont AS. Large-scale chromatin unfolding and remodeling induced by VP16 acidic activation domain. J Cell Biol. 1999;145(7):1341–54. doi: 10.1083/jcb.145.7.1341 10385516

26. Vogel JL, Kristie TM. The dynamics of HCF-1 modulation of herpes simplex virus chromatin during initiation of infection. Viruses. 2013;5(5):1272–91. doi: 10.3390/v5051272 23698399

27. Gu B, DeLuca N. Requirements for activation of the herpes simplex virus glycoprotein C promoter in vitro by the viral regulatory protein ICP4. J Virol. 1994;8(10):e78242.

28. Wagner LM, DeLuca NL. Temporal association if herpes simplex virus ICP4 with cellular complexes functioning at multiple steps in PolII transcription. PLOS One. 2013;108(46):18820–4.

29. Kalamvoki M, Roizman B. The histone acetyltransferase CLOCK is an essential component of the herpes simplex virus 1 transcriptome that includes TFIID, ICP4, ICP27, and ICP22. J Virol. 2011;85(18):9472–7. doi: 10.1128/JVI.00876-11 21734043

30. Lomonte P, Sullivan KF, Everett RD. Degradation of nucleosome-associated centromeric histone H3-like protein CENP-A induced by herpes simplex virus type 1 protein ICP0. J Biol Chem. 2001;276(8):5829–35. doi: 10.1074/jbc.M008547200 11053442

31. Lomonte P, Morency E. Centromeric protein CENP-B proteasomal degradation induced by the viral protein ICP0. FEBS Lett. 2007;581(4):658–62. doi: 10.1016/j.febslet.2007.01.027 17258208

32. Cliffe AR, Knipe DM. Herpes simplex virus ICP0 promotes both histone removal and acetylation on viral DNA during lytic infection. J Virol. 2008;82(24):12030–8. doi: 10.1128/JVI.01575-08 18842720

33. Ferenczy MW, DeLuca NA. Reversal of heterochromatic silencing of quiescent herpes simplex virus type 1 by ICP0. J Virol. 2011;85(7):3424–35. doi: 10.1128/JVI.02263-10 21191021

34. Ferenczy MW, Ranayhossaini DJ, Deluca NA. Activities of ICP0 involved in the reversal of silencing of quiescent herpes simplex virus 1. J Virol. 2011;85(10):4993–5002. doi: 10.1128/JVI.02265-10 21411540

35. Guzowski JF, Wagner EK. Mutational analysis of the herpes simplex virus type 1 strict late UL38 promoter/leader reveals two regions critical in transcriptional regulation. J Virol. 1993;67(9):5098–108. 8394438

36. Huang CJ, Goodart SA, Rice MK, Guzowski JF, Wagner EK. Mutational analysis of sequences downstream of the TATA box of the herpes simplex virus type 1 major capsid protein (VP5/UL19) promoter. J Virol. 1993;67(9):5109–16. 8394439

37. Turner BM. Histone acetylation and an epigenetic code. Bioessays. 2000;22(9):836–45. doi: 10.1002/1521-1878(200009)22:9<836::AID-BIES9>3.0.CO;2-X 10944586

38. Berger SL. Histone modifications in transcriptional regulation. Curr Opin Genet Dev. 2002;12(2):142–8. doi: 10.1016/s0959-437x(02)00279-4 11893486

39. Cosgrove MS, Boeke JD, Wolberger C. Regulated nucleosome mobility and the histone code. Nat Struct Mol Biol. 2004;11(11):1037–43. doi: 10.1038/nsmb851 15523479

40. Henikoff S. Nucleosome destabilization in the epigenetic regulation of gene expression. Nat Rev Genet. 2008;9(1):15–26. doi: 10.1038/nrg2206 18059368

41. Oh J, Fraser NW. Temporal association of the herpes simplex virus genome with histone proteins during a lytic infection. J Virol. 2008;82(7):3530–7. doi: 10.1128/JVI.00586-07 18160436

42. Narayanan A, Ruyechan WT, Kristie TM. The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection. Proc Natl Acad Sci U S A. 2007;104(26):10835–40. doi: 10.1073/pnas.0704351104 17578910

43. Cabral JM, Oh HS, Knipe DM. ATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress. Elife. 2018;7.

44. Arbuckle JH, Kristie TM. Epigenetic repression of herpes simplex virus infection by the nucleosome remodeler CHD3. MBio. 2014;5(1):e01027–13. doi: 10.1128/mBio.01027-13 24425734

45. Liang Y, Quenelle D, Vogel JL, Mascaro C, Ortega A, Kristie TM. A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency. MBio. 2013;4(1):e00558–12. doi: 10.1128/mBio.00558-12 23386436

46. Liang Y, Vogel JL, Arbuckle JH, Rai G, Jadhav A, Simeonov A, et al. Targeting the JMJD2 histone demethylases to epigenetically control herpesvirus infection and reactivation from latency. Sci Transl Med. 2013;5(167):167ra5. doi: 10.1126/scitranslmed.3005145 23303604

47. Liang Y, Vogel JL, Narayanan A, Peng H, Kristie TM. Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med. 2009;15(11):1312–7. doi: 10.1038/nm.2051 19855399

48. Memedula S, Belmont AS. Sequential recruitment of HAT and SWI/SNF components to condensed chromatin by VP16. Curr Biol. 2003;13(3):241–6. doi: 10.1016/s0960-9822(03)00048-4 12573221

49. Kutluay SB, DeVos SL, Klomp JE, Triezenberg SJ. Transcriptional coactivators are not required for herpes simplex virus type 1 immediate-early gene expression in vitro. J Virol. 2009;83(8):3436–49. doi: 10.1128/JVI.02349-08 19176620

50. Poon AP, Gu H, Roizman B. ICP0 and the US3 protein kinase of herpes simplex virus 1 independently block histone deacetylation to enable gene expression. Proc Natl Acad Sci U S A. 2006;103(26):9993–8. doi: 10.1073/pnas.0604142103 16785443

51. Gu H, Liang Y, Mandel G, Roizman B. Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells. Proc Natl Acad Sci U S A. 2005;102(21):7571–6. doi: 10.1073/pnas.0502658102 15897453

52. Danaher RJ, Jacob RJ, Steiner MR, Allen WR, Hill JM, Miller CS. Histone deacetylase inhibitors induce reactivation of herpes simplex virus type 1 in a latency-associated transcript-independent manner in neuronal cells. J Neurovirol. 2005;11(3):306–17. doi: 10.1080/13550280590952817 16036811

53. Lomonte P, Thomas J, Texier P, Caron C, Khochbin S, Epstein AL. Functional interaction between class II histone deacetylases and ICP0 of herpes simplex virus type 1. J Virol. 2004;78(13):6744–57. doi: 10.1128/JVI.78.13.6744-6757.2004 15194749

54. Boeger H, Griesenbeck J, Strattan JS, Kornberg RD. Nucleosomes unfold completely at a transcriptionally active promoter. Mol Cell. 2003;11(6):1587–98. doi: 10.1016/s1097-2765(03)00231-4 12820971

55. Henikoff S, Henikoff JG, Sakai A, Loeb GB, Ahmad K. Genome-wide profiling of salt fractions maps physical properties of chromatin. Genome Res. 2009;19(3):460–9. doi: 10.1101/gr.087619.108 19088306

56. Diwan P, Lacasse JJ, Schang LM. Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors. J Virol. 2004;78(17):9352–65. doi: 10.1128/JVI.78.17.9352-9365.2004 15308730

57. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26(5):589–95. doi: 10.1093/bioinformatics/btp698 20080505

58. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. doi: 10.1093/bioinformatics/btp352 19505943

59. Amelio AL, McAnany PK, Bloom DC. A chromatin insulator-like element in the herpes simplex virus type 1 latency-associated transcript region binds CCCTC-binding factor and displays enhancer-blocking and silencing activities. J Virol. 2006;80(5):2358–68. doi: 10.1128/JVI.80.5.2358-2368.2006 16474142

60. Lang F, Li X, Vladimirova O, Hu B, Chen G, Xiao Y, et al. CTCF interacts with the lytic HSV-1 genome to promote viral transcription. Sci Rep. 2017;7:39861. doi: 10.1038/srep39861 28045091

61. Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC, et al. Active genes are tri-methylated at K4 of histone H3. Nature. 2002;419(6905):407–11. doi: 10.1038/nature01080 12353038

62. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–5. doi: 10.1038/47412 10638745

63. Henikoff S, Strahl BD, Warburton PE. Epigenomics: a roadmap to chromatin. Science. 2008;322(5903):853.

64. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–80. doi: 10.1126/science.1063127 11498575

65. Placek BJ, Huang J, Kent JR, Dorsey J, Rice L, Fraser NW, et al. The histone variant H3.3 regulates gene expression during lytic infection with herpes simplex virus type 1. J Virol. 2009;83(3):1416–21. doi: 10.1128/JVI.01276-08 19004946

66. Knipe DM, Cliffe A. Chromatin control of herpes simplex virus lytic and latent infection. Nat Rev Microbiol. 2008;6(3):211–21. doi: 10.1038/nrmicro1794 18264117

67. Sekine E, Schmidt N, Gaboriau D, O'Hare P. Spatiotemporal dynamics of HSV genome nuclear entry and compaction state transitions using bioorthogonal chemistry and super-resolution microscopy. PLoS Pathog. 2017;13(11):e1006721. doi: 10.1371/journal.ppat.1006721 29121649

68. Conn KL, Hendzel MJ, Schang LM. Core histones H2B and H4 are mobilized during infection with herpes simplex virus 1. J Virol. 2011;85(24):13234–52. doi: 10.1128/JVI.06038-11 21994445

69. Conn KL, Hendzel MJ, Schang LM. Linker histones are mobilized during infection with herpes simplex virus type 1. J Virol. 2008;82(17):8629–46. doi: 10.1128/JVI.00616-08 18579611

70. Conn KL, Hendzel MJ, Schang LM. The differential mobilization of histones H3.1 and H3.3 by herpes simplex virus 1 relates histone dynamics to the assembly of viral chromatin. PLoS Pathog. 2013;9(10):e1003695. doi: 10.1371/journal.ppat.1003695 24130491

71. Huang J, Kent JR, Placek B, Whelan KA, Hollow CM, Zeng PY, et al. Trimethylation of histone H3 lysine 4 by Set1 in the lytic infection of human herpes simplex virus 1. J Virol. 2006;80(12):5740–6. doi: 10.1128/JVI.00169-06 16731913

72. Roizman B. The checkpoints of viral gene expression in productive and latent infection: the role of the HDAC/CoREST/LSD1/REST repressor complex. J Virol. 2011;85(15):7474–82. doi: 10.1128/JVI.00180-11 21450817

73. Coleman HM, Connor V, Cheng ZS, Grey F, Preston CM, Efstathiou S. Histone modifications associated with herpes simplex virus type 1 genomes during quiescence and following ICP0-mediated de-repression. J Gen Virol. 2008;89(Pt 1):68–77. doi: 10.1099/vir.0.83272-0 18089730

74. Ferenczy MW, DeLuca NA. Epigenetic modulation of gene expression from quiescent herpes simplex virus genomes. J Virol. 2009;83(17):8514–24. doi: 10.1128/JVI.00785-09 19535445

75. Kobiler O, Lipman Y, Therkelsen K, Daubechies I, Enquist LW. Herpesviruses carrying a Brainbow cassette reveal replication and expression of limited numbers of incoming genomes. Nat Commun. 2010;1:146. doi: 10.1038/ncomms1145 21266996

76. Kobiler O, Brodersen P, Taylor MP, Ludmir EB, Enquist LW. Herpesvirus replication compartments originate with single incoming viral genomes. MBio. 2011;2(6).

77. Cohen EM, Kobiler O. Gene Expression Correlates with the Number of Herpes Viral Genomes Initiating Infection in Single Cells. PLoS Pathog. 2016;12(12):e1006082. doi: 10.1371/journal.ppat.1006082 27923068

78. Shapira L, Ralph M, Tomer E, Cohen S, Kobiler O. Histone Deacetylase Inhibitors Reduce the Number of Herpes Simplex Virus-1 Genomes Initiating Expression in Individual Cells. Front Microbiol. 2016;7:1970. doi: 10.3389/fmicb.2016.01970 27999572

79. Cohen C, Corpet A, Roubille S, Maroui MA, Poccardi N, Rousseau A, et al. Promyelocytic leukemia (PML) nuclear bodies (NBs) induce latent/quiescent HSV-1 genomes chromatinization through a PML NB/Histone H3.3/H3.3 Chaperone Axis. PLoS Pathog. 2018;14(9):e1007313. doi: 10.1371/journal.ppat.1007313 30235352

80. Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J. CTCF-dependent chromatin boundary element between the latency-associated transcript and ICP0 promoters in the herpes simplex virus type 1 genome. J Virol. 2007;81(10):5192–201. doi: 10.1128/JVI.02447-06 17267480

81. Ertel MK, Cammarata AL, Hron RJ, Neumann DM. CTCF occupation of the herpes simplex virus 1 genome is disrupted at early times postreactivation in a transcription-dependent manner. J Virol. 2012;86(23):12741–59. doi: 10.1128/JVI.01655-12 22973047

82. Han F, Miyagawa Y, Verlengia G, Ingusci S, Soukupova M, Simonato M, et al. Cellular Antisilencing Elements Support Transgene Expression from Herpes Simplex Virus Vectors in the Absence of Immediate Early Gene Expression. J Virol. 2018;92(17).

83. Jenuwein T, Forrester WC, Fernandez-Herrero LA, Laible G, Dull M, Grosschedl R. Extension of chromatin accessibility by nuclear matrix attachment regions. Nature. 1997;385(6613):269–72. doi: 10.1038/385269a0 9000077

84. Schwartz YB, Cavalli G. Three-Dimensional Genome Organization and Function in Drosophila. Genetics. 2017;205(1):5–24. doi: 10.1534/genetics.115.185132 28049701

85. Arope S, Harraghy N, Pjanic M, Mermod N. Molecular characterization of a human matrix attachment region epigenetic regulator. PLoS One. 2013;8(11):e79262. doi: 10.1371/journal.pone.0079262 24244463

86. Ma Z, Li M, Roy S, Liu KJ, Romine ML, Lane DC, et al. Chromatin boundary elements organize genomic architecture and developmental gene regulation in Drosophila Hox clusters. World J Biol Chem. 2016;7(3):223–30. doi: 10.4331/wjbc.v7.i3.223 27621770

87. Silva L, Cliffe A, Chang L, Knipe DM. Role for A-type lamins in herpesviral DNA targeting and heterochromatin modulation. PLoS Pathog. 2008;4(5):e1000071. doi: 10.1371/journal.ppat.1000071 18497856

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