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HBV cccDNA转录调控机制与抗HBV治疗前景

陈娟 黄爱龙

引用本文:
Citation:

HBV cccDNA转录调控机制与抗HBV治疗前景

DOI: 10.3969/j.issn.1001-5256.2019.06.004
基金项目: 

国家自然科学基金(81672012,81871656,818110109); 

详细信息
  • 中图分类号: R512.62

Epigenetic regulation of hepatitis B virus cccDNA and related prospects for antiviral therapy

Research funding: 

 

  • 摘要: 以微染色体形式存在的HBV共价闭合环状DNA(cccDNA)在肝细胞核内持续稳定的存在,被认为是HBV感染慢性化、抗病毒治疗无法清除病毒以及停药后肝炎复发的最主要原因。然而,现有各种抗病毒治疗方案中,缺少以cccDNA本身或形成、转录等环节为靶点的药物,因此,靶向cccDNA环节的治疗策略是急需填补的空白。随着对cccDNA微染色体上组蛋白表观遗传修饰的逐步解析,表观遗传治疗也有望成为HBV新的潜在治疗方向。主要关注了HBV DNA甲基化和cccDNA组蛋白修饰的研究现状和发展方向,试图为HBV表观遗传治疗提供思路。

     

  • [1]Polaris Observatory Collaborators.Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016:Amodelling study[J].Lancet Gastroenterol Hepatol, 2018, 3 (6) :383-403.
    [2]LIN CL, YANG HC, KAO JH.Hepatitis B virus:New therapeutic perspectives[J].Liver Int, 2016, 36 (Suppl 1) :85-92.
    [3]GERLICH WH, ROBINSON WS.Hepatitis B virus contains protein attached to the 5'terminus of its complete DNA strand[J].Cell, 1980, 21 (3) :801-809.
    [4]MOLNAR-KIMBER KL, SUMMERS J, TAYLOR JM, et al.Protein covalently bound to minus-strand DNA intermediates of duck hepatitis B virus[J].J Virol, 1983, 45 (1) :165-172.
    [5]MASON WS, HALPERN MS, ENGLAND JM, et al.Experimental transmission of duck hepatitis B virus[J].Virology, 131 (1983) :375-384.
    [6]MILLER RH, ROBINSON WS.Hepatitis B virus DNA forms in nuclear and cytoplasmic fractions of infected human liver[J].Virology, 1983, 131 (2) :375-384.
    [7]TAGAWA M, OMATA M, YOKOSUKA O, et al.Early events in duck hepatitis B virus infection.Sequential appearance of viral deoxyribonucleic acid in the liver, pancreas, kidney, and spleen[J].Gastroenterology, 1985, 89 (6) :1224-1229.
    [8]TUTTLEMAN JS, POURCEL C, SUMMERS J.Formation of the pool of covalently closed circular viral DNA in hepadnavirusinfected cells[J].Cell, 1986, 47 (3) :451-460.
    [9]BOCK CT, SCHRANZ P, SCHRDER CH, et al.Hepatitis Bvirus genome is organized into nucleosomes in the nucleus of the infected cell[J].Virus Genes, 1994, 8 (3) :215-229.
    [10]NEWBOLD JE, XIN H, TENCZA M, et al.The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes[J].J Virol, 1995, 69 (6) :3350-3357.
    [11]ZHANG Y, LI C, ZHANG Y, et al.Comparative analysis of CpG islands among HBV genotypes[J].PLo S One, 2013, 8 (2) :e56711.
    [12]ZHANG Y, MAO R, YAN R, et al.Transcription of hepatitis Bvirus covalently closed circular DNA is regulated by CpG methylation during chronic infection[J].PLo S One, 2014, 9 (10) :e110442.
    [13]JAIN S, CHANG TT, CHEN S, et al.Comprehensive DNAmethylation analysis of hepatitis B virus genome in infected liver tissues[J].Sci Rep, 2015, 5:10478.
    [14]GUO Y, LI YN, ZHAO JR, et al.HBc binds to the CpGislands of HBV cccDNA and promotes an epigenetic permissive state[J].Epigenetics, 2011, 6 (6) :720-726.
    [15]LEE H, JEONG H, LEE SY, et al.Hepatitis B virus X protein stimulates virus replication via DNA methylation of the C-1619in covalently closed circular DNA[J].Mol Cells, 2019, 42 (1) :67-78.
    [16]IMAM H, KHAN M, GOKHALE NS, et al.N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle[J].Proc Natl Acad Sci U S A, 2018, 115 (35) :8829-8834.
    [17]MATSUDA Y, ICHIDA T.p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis[J].Med Mol Morphol, 2006, 39 (4) :169-175.
    [18]KOUZARIDES T.Chromatin modifications and their function[J].Cell, 2007, 128 (4) :693-705.
    [19]RODRGUEZ-PAREDES M, ESTELLER M.Cancer epigenetics reaches mainstream oncology[J].Nat Med, 2011, 17 (3) :330-339.
    [20]ZHANG W, CHEN J, WU M, et al.PRMT5 restricts hepatitis Bvirus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation[J].Hepatology, 2017, 66 (2) :398-415.
    [21]BEDFORD MT, RICHARD S.Arginine methylation an emerging regulator of protein function[J].Mol Cell, 2005, 18 (3) :263-272.
    [22]VIVEKANANDAN P, DANIEL HD, KANNANGAI R, et al.Hepatitis B virus replication induces methylation of both host and viral DNA[J].J Virol, 2010, 84 (9) :4321-4329.
    [23]RIVIRE L, GEROSSIER L, DUCROUX A, et al.HBx relieves chromatin-mediated transcriptional repression of hepatitis Bviral cccDNA involving SETDB1 histone methyltransferase[J].J Hepatol, 2015, 63 (5) :1093-1102.
    [24]DUCROUX A, BENHENDA S, RIVIRE L, et al.The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B virus and herpes simplex virus type 1[J].PLo S Pathog, 2014, 10 (9) :e1004343.
    [25]ALARCON V, HERNNDEZ S, RUBIO L, et al.The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state[J].Sci Rep, 2016, 6:25901.
    [26]PRADEEPA MM, GRIMES GR, KUMAR Y, et al.Histone H3globular domain acetylation identifies a new class of enhancers[J].Nat Genet, 2016, 48 (6) :681-686.
    [27]POLLICINO T, BELLONI L, RAFFA G, et al.Hepatitis B virus replication is regulated by the acetylation status of hepatitis Bvirus cccDNA-bound H3 and H4 histones[J].Gastroenterology, 2006, 130 (3) :823-837.
    [28]BELLONI L, ALLWEISS L, GUERRIERI F, et al.IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome[J].J Clin Invest, 2012, 122 (2) :529-537.
    [29]REN JH, HU JL, CHENG ST, et al.SIRT3 restricts hepatitis Bvirus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3-9 homolog 1 and SET domain containing 1A histone methyltransferases[J].Hepatology, 2018, 68 (4) :1260-1276.
    [30]HONG X, KIM ES, GUO H.Epigenetic regulation of hepatitis B virus covalently closed circular DNA:Implications for epigenetic therapy against chronic hepatitis B[J].Hepatology, 2017, 66 (6) :2066-2077.
    [31]BELLONI L, POLLICINO T, de NICOLA F, et al.Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function[J].Proc Natl Acad Sci U S A, 2009, 106 (47) :19975-19979.
    [32]WEI W, LIU X, CHEN J, et al.Class I histone deacetylases are major histone decrotonylases:Evidence for critical and broad function of histone crotonylation in transcription[J].Cell Res, 2017, 27 (7) :898-915.
    [33]WANG Y, GUO YR, LIU K, et al.KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase[J].Nature, 2017, 552 (7684) :273-277.
    [34]KEBEDE AF, NIEBORAK A, SHAHIDIAN LZ, et al.Histone propionylation is a mark of active chromatin[J].Nat Struct Mol Biol, 2017, 24 (12) :1048-1056.
    [35]ISHIGURO T, TANABE K, KOBAYASHI Y, et al.Malonylation of histone H2A at lysine 119 inhibits Bub1-dependent H2Aphosphorylation and chromosomal localization of shugoshin proteins[J].Sci Rep, 2018, 8 (1) :7671.
    [36]LU Y, XU Q, LIU Y, et al.Dynamics and functional interplay of histone lysine butyrylation, crotonylation, and acetylation in rice under starvation and submergence[J].Genome Biol, 2018, 19 (1) :144.
    [37]XU YM, DU JY, LAU AT.Posttranslational modifications of human histone H3:An update[J].Proteomics, 2014, 14 (17-18) :2047-2060.
    [38]JBARA M, GUTTMANN-RAVIV N, MAITY SK, et al.Total chemical synthesis of methylated analogues of histone 3 revealed KDM4D as a potential regulator of H3K79me3[J].Bioorg Med Chem, 2017, 25 (18) :4966-4970.
    [39]DALL'OLIO F, TRINCHERA M.Epigenetic bases of aberrant glycosylation in cancer[J].Int J Mol Sci, 2017, 18 (5) :998.
    [40]KONOPLEVA M, LETAI A.BCL-2 inhibition in AML:An unexpected bonus?[J].Blood, 2018, 132 (10) :1007-1012.
    [41]SANTINI V.How I treat MDS after hypomethylating agent failure[J].Blood, 2019, 133 (6) :521-529.
    [42]STONE ML, CHIAPPINELLI KB, LI H, et al.Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden[J].Proc Natl Acad Sci U S A, 2017, 114 (51) :e10981-e10990.
    [43]LIU M, ZHANG L, LI H, et al.Integrative epigenetic analysis reveals therapeutic targets to the DNA methyltransferase inhibitor guadecitabine (SGI-110) in hepatocellular carcinoma[J].Hepatology, 2018, 68 (4) :1412-1428.
    [44]SU Y, HOPFINGER NR, NGUYEN TD, et al.Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors[J].J Exp Clin Cancer Res, 2018, 37 (1) :314.
    [45]SONG Q, LI M, FAN C, et al.A novel benzamine lead compound of histone deacetylase inhibitor ZINC24469384 can suppresses HepG2 cells proliferation by upregulating NR1H4[J].Sci Rep, 2019, 9 (1) :2350.
    [46]SUN G, MACKEY LV, COY DH, et al.The histone deacetylase inhibitor vaproic acid induces cell growth arrest in hepatocellular carcinoma cells via suppressing notch signaling[J].JCancer, 2015, 6 (10) :996-1004.
    [47]LOPES-COELHO F, SILVA F, HIPLITO A, et al.Acetylation drives hepatocyte nuclear factor 1 beta stability by blocking proteasome-mediated degradation[J].J Cell Biochem, 2019, 120 (6) :9337-9344.
    [48]OZAKI T, WU D, SUGIMOTO H, et al.Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNAdamage[J].Cell Death Dis, 2013, 4:e610.
    [49]MARKS PA, XU WS.Histone deacetylase inhibitors:Potential in cancer therapy[J].J Cell Biochem, 2009, 107 (4) :600-608.
    [50]BLAGITKO-DORFS N, SCHLOSSER P, GREVE G, et al.Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors:Predominant synergistic gene downregulation associated with gene body demethylation[J].Leukemia, 2019, 33 (4) :945-956.
    [51]HUANG D, CUI L, AHMED S, et al.An overview of epigenetic agents and natural nutrition products targeting DNA methyltransferase, histone deacetylases and microRNAs[J].Food Chem Toxicol, 2019, 123:574-594.
    [52]BROCKS D, SCHMIDT CR, DASKALAKIS M, et al.Erratum:DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats[J].Nat Genet, 2017, 49 (11) :1661.
    [53]CHOVANEC M, TAZA F, KALRA M, et al.Incorporating DNAmethyltransferase inhibitors (DNMTis) in the treatment of genitourinary malignancies:A systematic review[J].Target Oncol, 2018, 13 (1) :49-60.
    [54]BRUYER A, MAES K, HERVIOU L, et al.DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells[J].Br JCancer, 2018, 118 (8) :1062-1073.
    [55]CHEN K, LIU J, LIU S, et al.Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity[J].Cell, 2017, 170 (3) :492-506.e414.
    [56]ALCENDOR RR, KIRSHENBAUM LA, IMAI S, et al.Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes[J].Circ Res, 2004, 95 (10) :971-980.
    [57]WEI ZQ, ZHANG YH, KE CZ, et al.Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation[J].World J Gastroenterol, 2017, 23 (34) :6252-6260.
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  • 收稿日期:  2019-04-04
  • 出版日期:  2019-06-20
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