摘要
在过去的三十年里,表观遗传学是生命科学研究的一个热点,产生了许多重大的研究成果。但是病毒学家们似乎对此无动于衷。直到现在,我们能找到的有关病毒的表观遗传学调控的文章都很有限。在这里,比起有潜伏感染期的单纯疱疹病毒(HSV)、乙型肝炎病毒(HBV)、Epstein-Barr病毒(EBV)和人类乳头状瘤病毒(HPV),裂解性复制病毒复制周期中的表观遗传学调控更少被关注。本文重点研究了杆状病毒苜蓿银纹夜蛾核型多角体病毒(Autographa californica multicapsid nucleopolyhedrosis, AcMNPV)在昆虫细胞中进行裂解性复制时的一些表观遗传学现象,包括病毒小染色体结构、组蛋白乙酰化修饰和DNA甲基化修饰在杆状病毒的复制和基因表达中的作用。
首先,我们证明了病毒小染色体结构和组蛋白乙酰化修饰在病毒基因转录中的作用。我们证实插入在病毒polyhedrin位点下游的鸡β-珠蛋白5'-HS4绝缘子(HS4)能显著提高polyhedrin启动子控制的报告基因的表达水平。当使用增强型绿色荧光蛋白(egfp)作为报告基因时,在感染后72h和96h,带HS4的重组病毒(AcEGFP-HS4)感染的昆虫细胞比不带HS4的对照病毒(AcEGFP)感染的细胞荧光分别高3倍和2.1倍。AcEGFP-HS4感染的细胞的egfp的mRNA水平也较AcEGFP感染的细胞高。在以萤火虫荧光素酶(firefly luciferase)或分泌型碱性磷酸酶(SEAP)为报告基因时,也观察到类似的表达水平的提高。进一步的机制研究表明,polyhedrin位点插入的HS4没有显著影响到病毒复制,而HS4的作用具有方向性且对组蛋白乙酰基转移酶抑制剂敏感。从DNaseⅠ敏感实验看出,HS4的存在显著提高了附近DNA对核酸酶的敏感性,但对距离较远的DNA没有作用。这些结果表明HS4可能通过改变在病毒形成的小染色体上邻近染色体结构来影响病毒基因表达。这一研究结果为提高杆状病毒-昆虫细胞表达系统表达目标蛋白的效率提供了新的途径,也明确提示在杆状病毒裂解性复制过程中,病毒小染色体的结构及组蛋白的乙酰化修饰对病毒基因的表达起着重要的作用。
为了揭示其它表观遗传学调控机制在杆状病毒复制过程中的作用,我们进一步研究了病毒复制过程中的DNA甲基化问题。我们首次证实病毒极早期基因ie0的转录受DNA甲基化调控。IE0是病毒的一个重要调控因子,在感染早期表达水平相对较高,而在感染晚期转录下调。这种表达水平的变化对病毒复制具有重要意义。我们发现：在感染后Oh (Ohp.i.) ie0启动子甲基化程度较高,8h p.i.时甲基化程度明显降低,但从18h p.i.起,这一区域甲基化程度又明显提高。体外DNA甲基化修饰实验表明DNA甲基化可以抑制ie0表达。DNA甲基转移酶抑制剂(DNMTi) DAC (50nM)的存在有助于维持ie0启动子低甲基化,并显著增加ie0的表达。这些研究结果证实启动子区域的DNA甲基化是ie0在感染晚期转录下调的原因,表明DNA甲基化在裂解性复制病毒基因表达的调控中也有重要作用。
为了全局性的了解DNA甲基化调控在病毒复制和基因转录中的作用,我们还研究了DAC对病毒复制和基因转录的影响。用50nM DAC处理,可使AcMNPV感染Sf9细胞时病毒效价下降到对照的1／30,并显著地延迟病毒DNA复制。DAC处理对病毒极早期基因的表达在感染后不同阶段有不同的影响。在2h p.i., DAC可以提高病毒极早期基因iel和ie2的表达,而在感染晚期,DAC抑制iel和ie2的转录。但是在整个复制周期中,DAC都提高ie0的转录。DAC对病毒滞早期基因转录的影响不均一,但抑制晚期基因的转录。DAC对病毒极晚期启动子的活性的抑制作用尤为明显。对于DAC抑制极晚期启动子的机制我们进行了进一步的研究,发现用质粒额外表达IE1可以缓解DAC的对极晚期启动子的抑制作用。这些数据,结合前面的结果和对IE0,IE1功能已有的认识,提示在感染的后期,DAC是通过抑制ie1的转录,同时避免ie0转录的降低,改变了IEO,IE1两个蛋白的相对比例,从而抑制了极晚期启动子的激活。这一研究结果表明DNA甲基化对病毒复制的调控作用可能主要是通过影响关键调控因子的转录来实现。
除了感染昆虫细胞以外,杆状病毒还能高效地侵入多种哺乳动物细胞。它作为一种新型哺乳动物转导载体正在受到越来越多的重视。但目标基因的表达沉默限制了杆状病毒这方面的应用。尽管人们早已发现组蛋白去乙酰基转移酶抑制剂可以提高杆状病毒介导的基因在哺乳动物细胞中的表达,但另一类引起表观遗传学修饰变化的药物,DNMTi却被报道没有这种效果。在本论文中,我们首次发现在病毒转导哺乳动物细胞前使用DNMTi AZA或DAC处理细胞,在多种哺乳动物细胞中杆状病毒介导的基因的表达水平均有四倍的提高；但如果添加药物的时间推迟,则其提高表达水平的作用会减弱乃至消失。同时在病毒接种期间有DNMTi的存在对其发挥作用至关重要。进一步的结果表明DNMTi可能是通过抑制细胞对病毒DNA降解起作用。这项研究为提高杆状病毒载体在哺乳动物细胞中应用的效果提供了新途径,也为揭示杆状病毒与哺乳动物细胞的作用关系,认识哺乳动物细胞对非特异性入侵物的反应及机理提供了新的数据。
In the last three decades, epigentics has been one of the fast developing areas in life science. Many great results were reported. However, virologists seem to be spectators in this field. Until recently, only a few reports about viral epigenetic regulation could be found. Compared with viruses with latent infection phase, such as herpes simplex virus (HSV), hepatitis B virus (HBV), Epstein-Barr virus (EBV) and human papillomavirus (HPV), less concern was given to the epigenetic regulation in the replication of lytic viruses. In this dissertation, we focused on epigentics regulation of baculovirus AcMNPV(Autographa californica multicapsid nucleopolyhedrovirus) during its lytic infection in insect cells. We studied the roles of viral minichromosome structure, histone acetylation and DNA methylation in viral gene expression and virus replication.
We first studied the roles of viral minichromosome structure and histone acetylation in viral gene expression. We found that chickenβ-globin 5'-HS4 insulator (HS4), which was placed downstream of the polyhedrin promoter-directed foreign gene expression cassette in AcMNPV, markedly increased the expression of reporter genes. When enhanced green fluorescence protein gene (egfp) was used as the reporter gene, cells infected by the recombinant virus with HS4 (AcEGFP-HS4) showed 3.0 and 2.1-fold stronger fluorescence than that by the control virus without HS4 (AcEGFP) at 72 and 96 h post infection, respectively. The level of egfp mRNA was also much higher in cells infected by AcEGFP-HS4 than that by AcEGFP. An increase in gene expression was also seen when firefly luciferase gene or secreted alkaline phosphatase gene was used as a reporter. The insertion of HS4 in the polyhedrin locus has no significant effect on virus replication. The effect of HS4 was orientation-dependent, and sensitive to inhibitors of histone acetyltransferase. In DNase I sensitivity assay, HS4 significantly increased the sensitivity of neighbouring DNA to nuclease, but had little effect on DNA of a distal locus. These results suggested that HS4 insulator might affect baculovirus gene expression by modifying the structure of neighbouring chromatin in the virus minichromosome. These results provided a new method to improve baculovirus-insect cell expression system, and clearly suggested viral minichromosome and histone acetylation play an important role in virus replication and viral gene expression.
To analyse other epigenetic regulation mechanisms in baculovirus replication, we then investigated DNA methylation during virus replication. We for the first time showed that the expression of viral immediate-early gene ieO was affected by the DNA methylation in the promoter area. IEO was an important viral regulator that was expressed at relatively higher level at the early phase of infection, and then down-regulated at late stage. The down-regulation of ieO was known to be imporant for normal virus replication. We found that ieO promoter was hypermethylated Oh p.i., hypomethylated 8h p.i., and back to hypermethylated state again after 18h p.i. In vitro DNA methylation test showed that DNA methylation inhibited ieO expression. Treatment with 50nM DAC, a kind of DNA methyltransferase inhibitor (DNMTi) maintained the hypomethylation of ieO promoter and increased ieO expression. These results indicated that DNA meythlation in the ieO promoter contributed to the down-regulation in ieO expression at the late phase of viral infection, and showed that DNA methylation played a role in the regulation of gene expression in lytic virus replication.
To understand the general relationship between DNA methylation and virus replication and viral gene expression, we also studied the effect of DNA methylation inhibitor, DAC on the virus replication and viral gene expression. Presence of 50nM DAC decreased viral titer to only 1/30 and delayed viral DNA replication significantly. Treatment with DAC has different effect on immediate early gene expression in different phases of infection. DAC increased the expression of immediate early gene iel and ie2 2h p.i., and inhibited their expression later. Meanwhile, DAC increased the expression of another immediate early gene, ie0, both early and late in the infection. The effect of DAC on the expression of viral delayed early genes was not uniformed, but it inhibited the expression of all late genes tested. DAC had more significant effect on the expression of viral very late genes, resulted in almost complete elimination of the protein production. The mechanism of DAC to inhibit very late gene expression was further studied. It was found that additional expression of IE1 by plasmid relieved the inhibitory effect of DAC on very late promoter. These data, in combination with results above, and known function of IEO and IE1 proteins, implied that DAC inhibited very late promoter by decreasing the expression iel, while while preventing the down-regulation of ieO expression. This will resulted in the improper ratio of IEO and IE1 in infected cells, which was known to be essential for the activation of viral very late promoter late in infection.These results suggested that viral DNA methylation might affect virus replication and viral gene expression by modifying the expression of a few important viral regulatory genes.
Apart from infecting insect cells, baculovirus could also enter many mammalian cells, too. In recent years, baculovirus has attracted more and more attentions as a gene delivery vector for mammalian cells. However, the silencing of target gene mediated by baculovirus limited its application. Although histone deacetylation inhibitors were known to improve baculovirus-mediated gene expression in mammalian cells for long time, another group of chemicals that induces epigenetic changes, DNMTi, was reported to have no such effect. In this dissertation, we for the first time found that DNMTi AZA or DAC improved baculovirus-mediated gene expression by fourfold or more in all four mammalian cell lines tested when they were added prior to virus inoculation. This improvement of gene expression was less significant or even abolished when drugs were added after virus inoculation. The further results indicated that DNMTi improved baculovirus-midated gene expression by inhibiting viral DNA degradation in transduced mammalian cells. This research provided a new method to improve the application of baculovirus vector in mammalian cells, and offered new insights to understand the relationship between baculovirus vector and mammalian cells, and the response to non-specific invasion by mammalian cells.
引文
[1]Holliday R. Epigentics:an overview [J]. Dev. Genet.,1994,15:453-457.
[2]Luger K, Mader AW, Richmond R, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8A resolution [J]. Nature,1997,389:251-260.
[3]Wu J, Grunstein M.25 years after the nucleosome model:chromatin modifications [J]. Trends. Biochem. Sci.,2000,25:619-623.
[4]Jenuwein T, Allis CD. Translating the histone code [J]. Science,2001,293:1074-1080.
[5]Turner BM. Cellular memory and the histone code [J]. Cell,2002,111:285-291.
[6]Strahl BD, Allis CD. The language of covalent histone modifications [J]. Nature,2000,403: 41-45.
[7]Turner BM. Histone acetylation and an epigenetic code [J]. BioEssays,2000,22:836-845.
[8]Roth SY, Denu JM, Allis CD. Histone acetyltransferases [J]. Annu. Rev. Biochem.,2001,70: 81-120.
[9]Grant PA, Berger SL. Histone acetyltransferase complexes [J]. Semin. Cell Dev. Biol.,1999, 10:169-177.
[10]Turner BM, Birley AJ, Lavender J. Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei [J]. Cell,1992,69:375-384.
[11]Braunstein M, Sobel RE, Allis CD, Turner BM, Broach JR. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern [J]. Mol Cell Biol.,1996,16:4349-4356.
[12]Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K. Genome-wide mapping of HATs and HDACs reveals distrinct functions in active and inactive genes [J]. Cell,2009, 138:1-13.
[13]Brownell JE, Allis CD. Special HATs for special occasions:linking histone acetylation to chromatin assembly and gene activation [J]. Curr. Opin. Genet. Dev.,1996,6:176-184.
[14]Roth SY, Denu JM, Allis CD. Histone acetyltransferases [J]. Ann. Rev. Biochem.,2001,70: 81-120.
[15]Verreault A, Kaufman PD, Kobayashi R, Stillman B. Nucleosomal DNA regulates the core-histone-binding subunit of the human Hatl acetyltransferase [J]. Curr. Biol.,1998,8: 96-108.
[16]Parthun MR, Widom J, Gottschling DE. The major cytoplasmic histone acetyltransferase in yeast:links to chromatin replication and histone metabolism [J]. Cell,1996,87:85-94.
[17]Lusser A, Eberharter A, Loidl A, Goralik-Schramel M, Horngacher M, Haas H, Loidl P. Analysis of the histone acetyltransferase B complex of maize embryos [J]. Nucl. Acids Res., 1999,27:4427-4435.
[18]Carrozza MJ, Utley RT, Workman JL, Cote J. The diverse functions of histone acetyltransferase complexes [J]. Trends Genet.,2003,19:321-329.
[19]Pandey R, Muller A, Napoli CA, Selinger DA, Pikaard CS, Richards EJ, Bender J, Mount DW, Jorgensen RA. Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes [J]. Nucl. Acids Res.,2002,30:5036-5055.
[20]Carrozza MJ, Utley RT, Workman JL, Cote J. The diverse functions of histone acetyltransferase complexes [J]. Trends Genet.,2003,19:321-329.
[21]Sterner DE, Berger SL. Acetylation of histones and transcription related factors [J]. Microbiol. Mol. Biol. Rev.,2000,64:435-459.
[22]Loidl P. Histone acetylation:facts and questions [J]. Chromosoma,1994,103:441-449.
[23]Boeger H, Griesenbeck J, Strattan JS, Kornberg RD. Nucleosomes unfold completely at a transcriptionally active promoter [J]. Mol. Cell,2003,11:1587-1598.
[24]Li B, Carey M, Workman JL. The role of chromatin during transcription [J]. Cell,2007,128: 707-719.
[25]Xu L, Glass CK, Rosenfeld MG. Coactivator and corepressor complexes in nuclear receptor function [J]. Curr. Opin. Genet. Dev.,1999,9:140-147.
[26]Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase [J]. Nature,2002,417:455-458.
[27]Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS, Wu CW. Histone deacetylases specially down-regulate p53-dependent gene activation [J]. J. Biol. Chem.,2000,275: 20436-20443
[28]de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs):characterization of the classical HDAC family [J]. Biochem. J., 2003,370:737-749.
[29]Yang XJ, Gregoire S. Class Ⅱ histone deacetylases:from sequence to function, regulation, and clinical implication [J]. Mol. Cell. Biol.,2005,25:2873-2884.
[30]Yang XJ, Seto E. The Rpd3/Hdal family of lysine deacetylases:from bacteria and yeast to mice and men [J]. Nat. Rev. Mol. Cell Biol.,2008,9:206-218.
[31]Kovacs JJ, Murphy PJM, Gaillard S, Zhao X, Wu J-T, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao T-P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor [J]. Mol. Cell,2005,18:601-607.
[32]Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla, K. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90:a novel basis for antileukemia activity of histone deacetylase inhibitors [J]. J. Biol. Chem.,2005,280:26729-26734.
[33]Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Gottlicher M. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis [J]. Cancer Cell,2004,5:455-463.
[34]Ropero S, Fraga MF, Ballestar E, Hamelin R, Yamamoto H, Boix-Chornet M, Caballero R, Alaminos M, Setien F, Paz MF, Herranz M, Palacios J, Arango D, Orntoft TF, Aaltonen LA, Schwartz S Jr, Esteller M. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition [J]. Nat. Genet.,2006,38:566-569
[35]Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, Saudou F. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation [J]. J. Neurosci.,2007,27:3571-3583.
[36]Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity [J]. Nature,2009,459:55-60.
[37]Marks PA, Xu WS. Histone deacetylase inhibitors:Potential in cancer therapy [J]. J. Cell. Biochem.,2009,107:600-608.
[38]Cummings JH. Short chain fatty acids in the human colon [J]. Gut,1981,22:763-779.
[39]Yoshida M, Kijima M, Akita M, Beppu T. Potent and special inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A [J]. J. Biol. Chem.,1990,265: 17174-17179.
[40]Stimson L, La Thangue NB. Biomarkers for predicting clinical response to HDAC inhibitors [J]. Cancer Lett.,2009,280:177-183.
[41]Balakrishnan L, Milavetz B. HDAC inhibitors stimulate viral transcription by multiple mechanisms [J]. Virol. J.,2008,5:43.
[42]Balasubramanyam K, Swaminathan V, Ranganathan A, Kundu TK. Small molecule modulators of histone acetyltransferase p300 [J]. J. Biol. Chem.,2003,278:19134-19140.
[43]Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A, Sadhale PP, Kundu TK. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alter global gene expression [J]. J. Biol. Chem.,2004,279:33716-33726.
[44]Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, Kundu TK. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription [J]. J. Biol. Chem.,2004,279: 51163-51171.
[45]Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclearfactor kappa B and Notch 1 in Raji cells [J]. Basic Clin. Pharmacol. Toxicol.,2007,101:427-433.
[46]Lau OD, Kundu TK, Soccio RE, Ait-Si-Ali S, Khalil EM, Vassilev A, Wolffe AP, Nakatani Y, Roeder RG. Cole PA. HATs off:selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF [J]. Mol. Cell,2000,5:589-595.
[47]Biel M, Kretsovali A, Karatzali, E, Papamathekis J, Giannis A. Design, synthesis and biological evaluation of a small-molecule inhibitor of the histone acetyltransferase Gcn5 [J]. Angew. Chem. Int. Ed. Engl.,2005,4:3974-3976.
[48]Stimson L, Rowlands MG, Newbatt YM, Smith NF, Raynaud FI, Rogers P, Bavetsias V, Gorsuch S, Jarman M, Bannister A, Kouzarides T, McDonald E, Workman P, Aherne G W. Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity [J]. Mol. Cancer Ther.,2005,4:1521-1532.
[49]Myers FA, Chong W, Evans DR, Throne AW, Crane-Robinson C. Acetylation of histone H2B Mirrors that of H4 and H3 at the chichen β-globin locus but not ar housekeeping genes [J]. J. Bio. Chem.,2008,278:36315-36322.
[50]Kametani Y, Wang L, Koduka K, Sato T, Kanato I, Habu S. Rapid histone deacetylation and transient HDAc association in the IL-2 promoter region of TSST-1-stimulated T cells [J]. Immuno. Lett.,2008,119:97-102.
[51]Han S, Lu J, Zhang Y, Cheng G, Han L, Wang X, Li L, Liu C, Huang B. Rescuitment of histone deacetylase 4 by transcription factors represses interleukin-5 transcription [J]. Biochem. J.,2006,400:439-448.
[52]Zhang Y, Reinberg D. Transcription regulation by histone methylation:interplay between different covalent modifications of the core histone tails. Genes Dev.,2001,15:2343-2360.
[53]Klose RJ, Zhang Y. Regulation of histone methylation by demethylimination and demethylation [J]. Nat. Rev. Mol. Cell Biol.,2007,8:307-318.
[54]Martin C, Zhang Y. The diverse functions of histone lysine methylation [J]. Nat. Rev. Mol. Cell. Biol.2005,6:838-849.
[55]Taverna SD, Ilin S, Rogers RS, Tanny JC, Lavender H, Li H, Baker L, Boyle J, Blair LP, Chait BT, Patel DJ, Aitchison JD, Tackett AJ, Allis CD. Yngl PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs [J]. Mol. Cell,2006,24:785-796.
[56]Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins [J]. Nature,2001,410:116-120.
[57]Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain [J]. Nature,2001,410:120-124.
[58]Huang Y, Fang J, Bedford MT, Zhang Y, Xu RM. Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A [J]. Science,2006,312:748-751.
[59]Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT, Badenhorst P, Wu C, Allis CD. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling [J]. Nature,2006,442:86-90.
[60]Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T. Regulation of chromatin structure by site-specific histone H3 methyltransferases [J]. Nature,2000,406:593-599.
[61]Bannister AJ, Schneider R, Kouzarides T. Histone methylation:dynamic or static? [J]. Cell, 2002,109:801-806.
[62]Bannister AJ, Kouzarides T. Reversing histone methylation [J]. Nature,2005,436: 1103-1106.
[63]Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR., Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1 [J]. Cell,2004,119: 941-953.
[64]Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH,Tempst P, Zhang Y. Histone demethylation by a family of JmjC domain-containing protein [J]. Nature,2006, 439:811-816.
[65]Mujtaba S, Manzur KL, Gurnon JR, Kang M, van Etten JL, Zhou M-M. Epigentic transcriptional repression of cellular genes by viral SET protein [J]. Nat. Cell Biol.,2008, 10:1114-1122.
[66]Szyf M. Epigenetics, DNA methylaton and chromatin modifying drugs [J]. Annu Rev Pharmacol Toxicol,2009,49:243-263.
[67]Ara AI, Xia M, Ramani K, Mato JM, Lu SC. S-adenosylmethionine inhibits lipopolysaccharideinduced gene expression via modulation of histone methylation [J]. Hepatology,2008,47:1655-1666.
[68]Huang Y, Greene E, Murray ST, Goodwin AC, Baylin SB, Woster PM, Casero RA Jr. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes [J]. Proc. Natl. Acad. Sci. U. S. A.,2007,104:8023-28.
[69]Pile L A, Lee FW, Wassarman DA. The histone deacetylase inhibitor trichostatin A infuences the development of Drosophila melanogaster [J]. Cell Mol. Life Sci.,2001,58: 1715-1718.
[70]Tao D, Lu J, Sun H, Zhao YM, Yuan ZG, Li XX, Huang BQ. Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 expression [J]. Acta Biochem Biophys Sin (Shanghai),2004,36:618-622.
[71]Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility [J]. Genes Dev.,2007,21:1790-1802.
[72]Forsberg EC, Bresnick EH. Histone aeetylation beyond promoters:long-range aeetylation patterns in the ehromatin world [J]. Bioessays,2001,23:820-830.
[73]Tsaj CC, Fondel JD. Nuclear receptor recruitment of histone-modilying enzymes to target gene promoters [J]. Vitam Horm,2004,68:93-122.
[74]McClintock B. Chromosome organization and genic expression [J]. Cold Spring Harbor Symp. Quant. Biol.,1951,16:13-47.
[75]Martienssen R, Baron A. Coordinate suppression of mutations caused by Robertson's Mutator transposons in maize [J]. Genetics,1994,136:1157-1170.
[76]Martienssen R, Barkan A, Taylor WC, Freeling M. Somatically heritable switches in the DNA modification of Mu transposable elements monitored with a suppressible mutant in maize [J]. Genes & Dev.,1990,4:331-343.
[77]Lee H-P, Chen Y-L, Shen H-C, Lo W-H, Hu Y-C. Baculovirus transduction of rat articular chondrocytes:roles of cell cycle [J]. J Gene Med.2007,9:33-43.
[78]Kunert N, Marhold J, Stanke J, Stach D, Lyko F. A Dnmt2-like protein mediates DNA methylation in Drosophila. Development [J].2003,130:5083-5090.
[79]Mandrioli M, Volpi N. The genome of the lepidopteran Mamestra brassicae has a vertebrate-like content of methylcytosine [J]. Genetica,2003,119:187-191.
[80]Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases [J]. Ann. Rev. Biochem., 2005,74:481-514.
[81]Bourc'his D, Xu G.L, Lin CS, Bollman, Bestor TH. Dnmt3L and the establishment of maternal genomic imprints [J]. Science,2001,294:2536-2539.
[82]Field LM, Lyko F, Mandrioli M, Prantera G DNA methylation in insect [J]. Insect Mol. Biol.,2004,13:109-115.
[83]Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine [J]. Int. J. Cancer.,2008,123:8-13.
[84]Ghoshal K, Datta J, Majumder S, Bai S, Kutay H, Motiwala T, Jacob ST. 5-AZA-Deoxycytidine induces selective degradation of DNA methyltransferase lby a ptoteasomal pathyway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal [J]. Mol. Cell. Biol.,2005,25:4727-4741.
[85]Fabre C, Grosjean J, Tailler M, Boehrer S, Ades L, Perfettini J, de Botton S, Fenaux P, Kroemer G. A novel effect of DNA methyltransferase and histone deacetylase inhibitors [J]. Cell Cycle,2008,7:2139-2145.
[86]Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase [J]. Nucl. Acids Res.,2003,31:2305-2312.
[87]Hoelzer K, Shackelton LA, Parrish CR. Presence and role of cytosine methylation in DNA viruses of animals [J]. Nucl. Acids Res.,2008,36:2825-2837.
[88]Suganuma T, Workman JL. Crosstalk among histone modification [J]. Cell,2008,135:604-607.
[89]Bayle JH, Crabtree GR. Protein acetylation:mmore than chromatin modification to regulate transcription [J]. Chem. Biol.,1997,4:885-888.
[1]Luger K, Mader AW, Richmond R, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8A resolution [J]. Nature,1997,389:251-260.
[2]Strahl BD, Allis CD. The language of covalent histone modifications [J]. Nature,2000,403: 41-45.
[3]Hake SB, Xiao A, Allis CD. Linking the epigenetic'language' of covalent histone modifications to cancer [J]. Br. J. Cancer,2004,90:761-769.
[4]Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK. Global histone modification patterns predict risk of prostate cancer recurrence [J]. Nature,2005,435: 1262-1266.
[5]Lieberman PM. Chromatin regulation of virus infection [J]. Trends Microbiol.,2006,14: 132-140.
[6]Mujtaba S, Manzur KL, Gurnon JR, Kang M, van Etten LJ, Zhou M-M. Epigenetic transcriptional repression of cellular genes by a viral SET protein [J]. Nat. Cell Bio.,2008, 10:1114-1122.
[7]Waga S, Stillman B. The DNA replication fork in eukaryotic cells [J]. Annu. Rev. Biochem., 1998,67:721-751.
[8]Jackson SP. Sensing and repairing DNA double-strand breaks [J]. Carcinogenesis,2002,23: 687-696.
[9]Tate VE, Philipson L. Parental adenovirus DNA accumulates in nucleosome-like structures in infected cells [J]. Nucl. Acids Res.,1979,6:2769-2785.
[10]Mirza MA, Weber J. Structure of adenovirus chromatin [J]. Biochim. Biophys. Acta,1982, 696:76-86
[11]Pryciak PM, Varmus HE. Nucleosomes, DNA-binding proteins, and DNA sequence modulate retroviral integration target site selection [J]. Cell,1992,69:769-780.
[12]Pruss D, Reeves R, Bushman FD, Wolffe AP. The influence of DNA and nucleosome structure on integration events directed by HIV integrase [J]. J. Biol. Chem.,1994,269: 25031-25041.
[13]Cereseto A, Manganaro L, Gutierrez MI, Terreni M, Fittipaldi A, Lusic M, Marcello A, Giacca M. Acetylation of HIV-1 integrase by p300 regulates viral integration [J]. EMBO J., 2005,24:3070-3081.
[14]Greger, JG, Katz RA, Ishov AM, Maul GG, Skalka AM. The cellular protein Daxx interacts with avian sarcoma virus integrase and viral DNA to repress viral transcription [J]. J. Virol., 2005,79:4610-4618.
[15]Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC. NFkappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation [J]. Embo. J.,2006,25:139-149.
[16]du Chene I, Basyuk E, Lin YL, Triboulet R, Knezevich A, Chable-Bessia C, Mettling C, Baillat V, Reynes J, Corbeau P, Bertrand E, Marcello A, Emiliani S, Kiernan R, Benkirane M. Suv39Hl and HP1 gamma are responsible for chromatin-mediated HIV-1 transcriptional silencing and post-integration latency [J]. Embo. J.,2007,26:424-435.
[17]Blazkova J, Trejbalova K, Gondois-Rey F, Halfon P, Philibert P, Guiguen A, Verdin E, Olive D, van Lint C, Hejnar J, Hirsch I. CpG methylation controls reactivation of HIV from latency [J]. PLoS Path.,2009,5:e1000554.
[18]Huttner NA, Girod A, Schnittger S, Schoch C, Hallek M, Buning H. Analysis of site-specific transgene integration following cotransduction with recombinant adeno-associated virus and a rep encoding plasmid [J]. J. Gene Med.,2003,5:120-129.
[19]. Ponnazhagan S, Erikson D, Kearns WG, Zhou SZ, Nahreini P. Lack of site-specific integration of the recombinant adeno-associated virus 2 genomes in human cells [J]. Hum. Gene Ther.,1997,8:275-284.
[20]Knipe DM, Cliffe A. Chromatin control of herpes simplex virus lytic and latent infection [J]. Nat. Rev. Microbiol.,2008,6:211-221.
[21]Chen Q, Lin L, Smith S, Huang J, Berger S, Zhou J. A CTCF-dependent chromatin boundary element exists between the LAT and ICP0 promoters in the HSV-1 genome [J]. J. Virol.2007,81:5192-5201.
[22]Day L, Chau CM, NebozhynM, Rennenkamp AJ, Showe M, Lieberman PM. Chromatin profiling of Epstein-Barr virus latency control region [J]. J. Virol.,2007,81:6389-6401.
[23]Lieberman PM. Chromatin organization and virus gene expression [J]. J. Cell. Physiol., 2008,216:295-302.
[24]Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, Levrero M. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones [J]. Gastroenterology,2006,130:823-837.
[25]Julien E, Herr W. A switch in mitotic histone H4 lysine 20 methylation status is linked to M phase defects upon loss of HCF-1 [J]. Mol. Cell,2004,14:713-725
[26]Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, Kitabayashi I, HerrW, Cleary ML. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression [J]. Mol. Cell. Biol.,2004,24:5639-5649.
[27]Gu H, Roizman B. Herpes simplex virus-infected cell protein 0 blocks the silencing of viral DNA by dissociating histone deacetylases from the CoREST-REST complex [J]. Proc. Natl. Acad. Sci. U. S. A.,2007,104:17134-17139.
[28]Nevels M, Paulus C, Shenk T. Human cytomegalovirus immediate-early 1 protein facilitates viral replication by antagonizing histone deacetylation [J]. Proc. Natl. Acad. Sci. U. S. A., 2004,101:17234-17239.
[29]Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK. Epigenetic reprogramming by adenovirus ela [J]. Science,2008,321:1086-1088.
[30]Bednarik DP, Cook JA, Pitha PM. Inactivation of the HIV LTR by DNA CpG methylation: Evidence for a role in latency [J]. EMBO. J.1990,9:1157-1164.
[31]Hoelzer K, Shackelton LA, Parrish CR. Presence and role of cytosine methylation in DNA viruses of animals [J]. Nucl. Acids Res.,2008,36:2825-2837.
[32]Kalla M, Schmeinck A, Bergbauer M, Pich D, Hammerschmidt W. AP-1 homolog BALF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of viral genome [J]. Proc. Natl. Acad. Sci. U. S. A.,2010,107:850-855.
[33]Vivekanandan P, Daniel HD, Kannangai R, Martinez-Murillo F, Torbenson M. Hepatitis B viral replication induces methylation of both host and viral DNA [J]. J. Virol., doi:10.1128/JVI.02280-09.
[34]MaCarty DM, Young Jr. SM, Samulski RJ. Integration of adeno-associated virus (AAV) and recombination AAV vector [J]. Annu. Rev. Genet.,2004,38:819-845.
[35]Wang X, Li L, Ding S, Huang X, Zhang J, Yin J, Zhong J. Chicken HS4 insulator significantly improves baculovirus-mediated foreign gene expression in insect cells by modifying the structure of neighboring chromatin in virus minichromosome [J]. J. Biotech., 2009,142:193-199.
[1]Miller LK. The Baculoviruses[M].1997, Plenum Press, New York.
[2]Tilakaratne N, Hardin SE, Weaver RF. Nucleotide sequence and transcript mapping of the HindⅢ F region of the Autographa californica nuclear polyhedrosis virus genome [J]. J. Gen. Virol.,1991,72:285-291.
[3]Kim D, Weaver RF. Transcription mapping and functional analysis of the protein tyrosine/serine phosphatase (PTPase) gene of the Autographa californica nuclear polyhedrosis virus [J]. Virology,1993,195:587-595.
[4]Laufs S, Lu A, Arrell K, Carstens EB. Autographa californica nuclear polyhedrosis virus p143 gene product is a DNA-binding protein [J]. Virology,1997,228:98-106.
[5]Blissard GW, Kogan PH, Wei R, Rohrmann GF. A synthetic early promoter from a baculovirus:roles of the TATA box and conserved start site CAGT sequence in basal levels of transcription [J]. Virology,1992,190:783-793.
[6]Beniya H, Funk CJ, Rohrmann GF, Weaver RF. Purification of a virus-induced RNA polymerase from Autographa californica nuclear polyhedrosis virus [J]. Virology,1996, 202:586-592.
[7]Ribeiro BM, Hutchinson K, Miller LK. A mutant baculovirus with temperature-sensitive IE-1 transregulatory protein [J]. J. Virol,1994,68:1075-1084.
[8]Victoria AO, Justin AW, Paul DF. The highly conserved basic domain Ⅰ of baculovirus IE1 is Rrequiredfor hr enhancer DNA binding and hr-dependent transactivation [J]. J. Virol., 2003,77:5668-5677.
[9]LaCount DJ, Friesenn PD. Role of early and late replication events in induction of apoptosis by baculoviruses [J]. J. Virol.,1997,71:1530-1537.
[10]Chisholm GE, Henner DJ. Multiple early transcripts and splicing of the Autographa californica nuclear polyhedrosis virus IE-1 gene [J]. J. Virol.,1988,62:3193-3200.
[11]Stewart TM, Huijskens I, Willis LG, Theilmann DA. The Autographa californica multiple nucleopolyhedrovirus ie0-ie1 gene complex is essential for wild-type virus replication, but either IE0 or IE1 can support virus growth [J]. J. Virol.,2005,79:4619-4629.
[12]Schultz KLW, Wetter JA, Fiore DC, Friesen PD. Transactivator IE1 is required for baculovirus early replication events that trigger apoptosis in permissive and nonpermissive cells [J]. J. Virol.,2009,83:262-272.
[13]Huijskens I, Li L, Willis LG, Theilmann DA. Role of AcMNPV IE0 in baculovirus very late gene activation [J]. Virology,2004,323:120-130.
[14]Lu A, Carsten EB. Immediately-early baculovirus genes transactivate the p143 gene promoter of Autographa californica nuclear polyhedrosis virus [J]. Virology,1993,195: 710-718.
[15]Prikhod'ko EA, Miller LK. Role of baculovirus IE2 and its RING finger in cell cycle arrest [J]. J.Virol.,1998,72:684-692.
[16]Prikhod'ko EA, Lu A, Wilson JA, Miller LK. In vivo and in vitro analysis of baculovirus ie-2 mutants [J]. J. Virol.,1999,73:2460-2468.
[17]Milks M, Washburn JO, Willis LG, Volkman LE, Theilmann DA. Deletion of pe38 attenuates AcMNPV genome replication, budded virus production, and virulence in heliothis virescens [J]. Virology,2003,310:224-234.
[18]Prikhod'ko EA, Miller LK. The baculovirus PE38 protein augments apoptosis induced by transactivator IE1 [J]. J. Virol.,1999,73:6691-6699.
[19]Xi Q, Wang J, Deng Q, Wang X. Characterization of AcMNPV with a deletion of me53 gene [J]. Virus Genes,2007,34:223-232.
[20]Adam LV, Kazuhiro O, George FR. Characterization of the replication of a baculovirus mutant lacking the DNA polymerase gene [J]. Virology,2005,331:175-180.
[21]Todd JW, Passarelli AL, Miller LK. Eighteen baculovirus genes, including lef-11, p35,39K, and p47, support late gene expression [J]. J. Virol.,1995,69:968-974.
[22]Kool M, Ahrens CH, Goldbach RW, Rohrmann GF, Vlak JM. Identification of genes involved in DNA replication of the Autographa californica baculovirus [J]. Proc. Natl. Acad. Sci. U. S. A.,1994,91:11212-11216.
[23]Lu A, Miller LK. The roles of eighteen baculovirus late expression factor genes in transcription and DNA replication [J]. J. Virol.,1995,69:975-982.
[24]Mikhailov VS. Helix-destabilizing properties of the baculovirus single-stranded DNA-binding protein (LEF-3) [J]. J. Virol.,2000,270:180-189.
[25]Guarino LA, Jin J, Dong W. Guanylyltransferase activity of the LEF-4 Subunit of baculovirus RNA polymerase [J]. J. Virol.,1998,72:10001-10010.
[26]Guarino LA, Dong W, Jin J. In Vitro Activity of the Baculovirus Late Expression Factor LEF-5 [J]. J. Virol.,2006,76:12663-12675.
[27]Guarino LA, Mistretta TA, Dong W. Baculovirus lef-12 is not required for viral replication [J]. J. Virol.,2002,76:12032-12043.
[28]Lin G, Blissard GW. Analysis of an Autographa californica nucleopolyhedrovirus lef-11 knockout:LEF-11 is essential for viral DNA replication [J]. J. Virol.,2002,76:2770-2779.
[29]Lin G, Blissard GW. Analysis of an Autographa californica multicapsid nucleopolyhedrovirus lef-6-null virus:LEF-6 is not essential for viral replication but appears to accelerate late gene transcription [J]. J. Virol.,2002,76:5503-5514.
[30]Rapp JC, Wilson JA, Miller LK. Nineteen baculovirus open reading frames, including LEF-12, support late gene expression [J]. J. Virol.,1998,72:10197-10206.
[31]Todd JW, Passarelli AL, Lu A, Miller LK. Factors regulating baculovirus late and very late gene expression in transient-expression assays [J]. J. Virol.,1996,70:2307-2317
[32]Li Y, Wang J, Deng R, Zhang Q, Yang K, Wang X. vlf-1 deletion brought AcMNPV to defect in nucleocapsid formation [J]. Virus Genes,2005,3:275-284.
[33]Goley ED, Ohkawa T, Mancuso J, Woodruff JB, D'Alessio JA, Cande WZ, Volkman LE, Welch MD. Dynamic nuclear actin assembly by Arp2/3 complex and a baculovirus WASP-like protein [J]. Science,2006,314:464-467.
[34]Passarelli AL, Guarino LA. Baculovirus late and very late gene regulation [J]. Curr. Drug. Target,2007,8:1103-1115.
[1]Chung JH, Whiteley M, Felsenfeld G A 5'element of the chicken β-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila [J]. Cell,1993,74:505-514.
[2]Chung JH, Bell AC, Felsenfeld G. Characterization of the chicken beta-globin insulator [J]. Proc. Natl. Acad. Sci. U. S. A.,1997,94:575-580.
[3]Gaszner M, Felsenfeld G Insulators:exploiting transcriptional and epigenetic mechanisms [J]. Nature Rev. Gentics.2006,7:703-713.
[4]Urbinati F, Arumugam P, Higashimoto T, Perumbeti A, Mitts K,Xia P, Malik P. Mechanism of reduction in titers from lentivirus vectors carrying large inserts in the 3'LTR [J]. Mol. Ther.,2009,17:1527-1536.
[5]Steinwaerder DS, Lieber A. Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo [J]. Gene Ther.,2000,7:556-567.
[6]McArthur M, Gerum S, Stamatoyannopoulos G Quantification of DNaseⅠ sensitivity by real-time PCR:quantitative analysis of DNaseⅠ-hypersensitivity of the mouse P-globin LCR [J]. J. Mol. Biol.2001,313:27-34.
[7]Peng Y, Song J, Lu J, Chen X. The histone deacetylase inhibitor sodium butyrate inhibits baculovirus-mediated transgene expression in Sf9 cells [J]. J.Biotechnol.2007,131: 180-187.
[8]West AG, Huang S, Gaszner M, Litt MD, Felsenfeld G Recruitment of histone modifications by USF proteins at vertebrate barrier element [J]. Mol. Cell,2004,16: 453-463.
[9]Roth SY, Denu JM, Allis CD. Histone acetyltransferases [J]. Annu. Rev. Biochem.,2001,70: 81-120.
[10]Lieberman PM. Chromatin organization and virus gene expression [J]. J. Cell.Physiol., 2008,216:295-302.
[11]Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A, Sadhale PP, Kundu TK. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alter global gene expression [J]. J. Biol. Chem.,2004,279:33716-33726.
[12]Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, Kundu TK. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription [J]. J. Biol. Chem.,2004,279: 51163-51171.
[13]Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G. Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells [J]. Basic Clin. Pharmacol. Toxicol.,2007,101:427-433.
[14]Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes [J]. Cell,2009, 138:1019-1031.
[15]Akimitsu N, Tanaka J, Pelletier J. Translation of nonstop mRNA is represses post-initiation in mammalian cells [J]. EMBO. J.,2007,26:2327-2338.
[16]Hanawa H, Yamamoto M, Zhao H, Shimada T, Persons DA. Opimized lentiviral vector design improves titer and transgene expression of vector containing the chicken β-globin locus HS4 insulator element [J]. Mol.Ther.,2009,17:667-674.
[17]Wu CP, Huang YR, Wang JY, Wu YL, Lo HR, Wang JC, Chao YC. AcMNPV LEF-2 is a capsid protein required for ampliation but not initiation of viral DNA replication [J]. J. Virol.,2010, Epub ahead of print.
[18]张静.提高重组杆状病毒表达系统的表达量和特异性的研究[D].上海：复旦大学,2006.
[19]李俪.提高杆状病毒介导的外源基因表达水平的研究[D].上海：复旦大学,2007.
[20]奥伯斯F.,金斯顿R.E.等著；精编分子生物学实验指南(颜子颖,王海林译.)[M].科学出版社,1998.
[21]McArthur M, Gerum S, Stamatoyannopoulos G. Quantification of DNasel sensitivity by real-time PCR:quantitative analysis of DNasel-hypersensitivity of the mouse (3-globin LCR [J]. J. Mol. Biol.,2001,313:27-34.
[22]Invitrogen, Protocol of Bac-to-Bac(?) Baculovirus Expression Systems.
[23]Wang L, Shan L, Yin J, Zhao ML, Su DM, Zhong J. The activation of lytic replication of Epstein-Barr virus by baculovirus-mediated gene transduction [J]. Arch. Virol.,2006,151: 2047-2053.
[24]薛庆善.体外培养的原理与技术[M].科学出版社,2001.
[25]Brown AE, Bugeon L, Crisanti A, Catteruccia F. Stable and heritable gene silencing in the malaria vector Anopheles stephensi [J].2003, Nucleic Acids Res.,31:e85
[26]Lieberman PM. Chromatin regulation of virus infection [J]. Trends Microbiol.,2006,14: 132-140.
[27]Shaner NC, Campbell RE, Steinbach PA, Giepmans BNG, Palmer AE, Tsie RY. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein [J]. Nat. Biotech.2004,22:1567-1572.
[28]Zhao H, Kim A, Song S, Dean A. Enhancer blocking by chicken β-globin 5'-HS4:role of enhancer strength and insulator nucleosome depletion [J]. J. Bio. Chem.,2006,281: 30573-30580.
[29]Litt MD, Simpson M, Gaszner M, Allis CD, Felsenfeld G. Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus [J]. Science, 2001,293:2453-2455.
[1]Huijskens I, Li L, Willis LG, Theilmann DA. Role of AcMNPV IEO in baculovirus very late gene activation [J]. Virology,2004,323:120-130.
[2]Kovas GR, Guarino LA, Summers MD. Novel regulatory properties of the IE1 and IEO transactivators encoded by the baculovirus Autographia califonica multicapsid nuclear polyhedosis virus [J]. J. Virol.,1991,65:5281-5288.
[3]Lu L, Du Q, Chejanovaky N. Reduced expression of the immediate-early IEO enables efficient replication of Autographia califonica multicapsid nucleopolyhedrovirus in poorly permissive Spodoptera littoralis cells. J. Virol.,2003,77:535-545.
[4]Hoelzer K, Shackelton LA, Parrish CR. Presence and role of cytosine methylation in DNA viruses of animals [J]. Nucl. Acids Res.,2008,36:2825-283.
[5]Field LM, Lyko F, Mandrioli M, Prantera G. DNA methylation in insect [J]. Insect Mol. Biol., 2004,13:109-115.
[6]Chisholm GE, Henner DJ. Multiple early transcripts and splicing of the Autographa californica nuclear polyhedrosis virus IE-1 gene [J]. J. Virol.,1988,62:3193-3200.
[7]Stewart TM, Huijskens I, Willis LG, Theilmann DA. The Autographa californica multiple nucleopolyhedrovirus ie0-ie1 gene complex is essential for wild-type virus replication, but either IEO or IE1 can support virus growth [J]. J. Virol.,2005,79:4619-4629.
[8]Leisy DJ, Rasmussen C, Owusu EO, Rohrmann GF.A mechanism of negative gene regulation in Autographa californica multinucleocapsid nuclear polyhedrosis virus [J]. J. Virol.,1997,72:5088-5094.
[9]Kunert N, Marhold J, Stanke J, Stach D, Lyko F. A Dnmt2-like protein mediates DNA methylation in Drosophila [J]. Development,2003,130:5083-5090.
[10]Lee H-P, Chen Y-L, Shen H-C, Lo W-H, Hu Y-C. Baculovirus transduction of rat articular chondrocytes:roles of cell cycle [J]. J Gene Med.,2007,9:33-43.
[11]Mandrioli M, Volpi N. The genome of the lepidopteran Mamestra brassicae has a vertebrate-like content of methylcytosine [J]. Genetica,2003,119:187-191.
[12]Lieberman PM. Chromatin regulation of virus infection [J]. Trends Microbiol.,2006,14: 132-140.
[13]奥伯斯F.,金斯顿R.E.等著；精编分子生物学实验指南(颜子颖,王海林译.)[M].科学出版社,1998.
[14]Passarelli AL, Guarino LA. Baculovirus late and very late gene regulation [J]. Curr. Drug. Target,2007,8:1103-1115.
[1]Steinwaerder DS, Lieber A. Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo [J]. Gene Ther.,2000,7:556-567.
[2]Ramezani A, Hawley TS, Hawley RG. Performance-and safety-enhanced lentiviral vectors containing the human interferon-β scaffold attachment region and the chinken β-globin insulator. Blood,2003,101:4717-4724.
[3]张静.提高重组杆状病毒表达系统的表达量和特异性的研究[D].上海：复旦大学,2006.
[4]Wang X, Yin J, Huang X, Zhong J. DNA methyltransferase inhibitors increase baculovirus-mediated gene expression in mammalian cells when applied before infection [J]. Anal. Biochem.,2009,396:322-324.
[5]Lu L, Du Q, Chejanovaky N. Reduced expression of the immediate-early IE0 enables efficient replication of Autographia califonica multicapsid nucleopolyhedrovirus in poorly permissive Spodoptera littoralis cells. J. Virol.,2003,77:535-545.
[6]Leisy DJ, Rasmussen C, Owusu EO, Rohrmann GF.A mechanism of negative gene regulation in Autographa californica multinucleocapsid nuclear polyhedrosis virus [J]. J. Virol.,1997,72:5088-5094.
[7]Kovas GR, Guarino LA, Summers MD. Novel regulatory properties of the IE1 and IE0 transactivators encoded by the baculovirus Autographia califonica multicapsid nuclear polyhedosis virus [J]. J. Virol.,1991,65:5281-5288.
[8]Passarelli AL, Guarino LA. Baculovirus late and very late gene regulation [J]. Curr. Drug. Target,2007,8:1103-1115.
[9]Stewart TM, Huijskens I, Willis LG, Theilmann DA. The Autographa californica multiple nucleopolyhedrovirus ie0-ie1 gene complex is essential for wild-type virus replication, but either IE0 or IE1 can support virus growth [J]. J. Virol.,2005,79:4619-4629.
[10]Kool M, Ahrens CH, Goldbach RW, Rohrmann GF, Vlak JM. Identification of genes involved in DNA replication of the Autographa californica baculovirus [J]. Proc. Natl. Acad. Sci. U. S. A.,1994,91:11212-11216.
[11]Lu A, Miller LK. The roles of eighteen baculovirus late expression factor genes in transcription and DNA replication [J]. J. Virol.,1995,69:975-982.
[12]Wu CP, Huang YR, Wang JY, Wu YL, Lo HR, Wang JC, Chao YC. AcMNPV LEF-2 is acapsid protein required for amplication but not initiation of viral DNA replication [J]. J. Virol.,2010, Epub ahead of print.
[1]Steinwaerder DS, Lieber A. Insulation from viral transcriptional regulatory elements improves inducible transgene expression from adenovirus vectors in vitro and in vivo [J]. Gene Ther.,2000,7:556-567.
[2]Urbinati F, Arumugam P, Higashimoto T, Perumbeti A, Mitts K,Xia P, Malik P. Mechanism of reduction in titers from lentivirus vectors carrying large inserts in the 3'LTR [J]. Mol. Ther.,2009,17:1527-1536.
[3]张静.提高重组杆状病毒表达系统的表达量和特异性的研究[D].上海：复旦大学,2006.
[4]Chung JH, Whiteley M, Felsenfeld G. A 5'element of the chicken β-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila [J]. Cell,1993,74:505-514.
[5]Lee H-P, Chen Y-L, Shen H-C, Lo W-H, Hu Y-C. Baculovirus transduction of rat articular chondrocytes:roles of cell cycle [J]. J Gene Med.2007,9:33-43.
[6]Field LM, Lyko F, Mandrioli M, Prantera G. DNA methylation in insect [J]. Insect Mol. Biol., 2004,13:109-115.
[7]Kitajima M, Hamazaki H, Miyano-Kurosaki N, Takaku H. Characterization of baculovirus Autographa californica multiple nuclear polyhedrosis virus infection in mammalian cells [J].Biochem. Biophys. Res. Commun.,2006,343:378-384.
[8]Luz-Madrigal A, Clapp C, Aranda J, Vaca J. In vivo transcription targeting into the retinal vasculature using recombination baculovirus carrying the human flt-1 promoter [J]. Virol. J. 2007,4:88.
[9]Hu Y-C. Baculoviral vector for gene delivery:a review. Curr. Gene Ther.,2008,8:54-65.
[10]Condreay JP, Witherspoon SM, Clay WC, Kost TA. Transient and stable gene expression in mammalian cells transduced with a recombinant baculovirus vector [J]. Proc. Natl. Acad. Sci.USA,1999,96:127-132.
[11]Chen G-Y, Shiah H-C, Su H-J, Chen C-Y, Chuang Y-J, Lo W-H, Huang J-L, Chuang C-K, Hwang S-M, Hu Y-C. Baculovirus transduction of mesenchymal stem cell trigger the toll-like receptor 3(TLR3) pathyway [J]. J. Virol.2009,83:10548-10556.
[12]Abe T, Hemmi H, Miyamoto H, Moriishi K, Tamura S, Takru H, Akira S, Matsuura Y. Involvement of the toll-like receptor 9 signaling pathyway in the induction of innate immunity by baculovirus [J]. J. Virol.,2005,79:2847-2858.
[13]Fabre C, Grosjean J, Tailler M, Boehrer S, Ades L, Perfettini J, de Botton S, Fenaux P, Kroemer G. A novel effect of DNA methyltransferase and histone deacetylase inhibitors [J]. Cell Cycle,2008,7:2139-2145.
[14]Trinchieri G, Sher A. Coorperation of toll-like receptor signals in innate immune defence [J]. Nat. Rev. Immunol.,2007,7:179-190.
[15]Hervas-Stubbs S, Rueda P, Lopez L, Leclerc C. Insect baculovirus strongly potentiate adaptive immune responses by inducing Type Ⅰ IFN [J]. J. Immunol.,2007,178:2361-2369.