It is well established that Epstein-Barr virus nuclear antigen 3C (EBNA3C) can act as a potent repressor of gene expression, but little is known about the sequence of events occurring during the repression process. To explore further the role of EBNA3C in gene repression–particularly in relation to histone modifications and cell factors involved–the three host genes previously reported as most robustly repressed by EBNA3C were investigated. COBLL1, a gene of unknown function, is regulated by EBNA3C alone and the two co-regulated disintegrin/metalloproteases, ADAM28 and ADAMDEC1 have been described previously as targets of both EBNA3A and EBNA3C. For the first time, EBNA3C was here shown to be the main regulator of all three genes early after infection of primary B cells. Using various EBV-recombinants, repression over orders of magnitude was seen only when EBNA3C was expressed. Unexpectedly, full repression was not achieved until 30 days after infection. This was accurately reproduced in established LCLs carrying EBV-recombinants conditional for EBNA3C function, demonstrating the utility of the conditional system to replicate events early after infection. Using this system, detailed chromatin immunoprecipitation analysis revealed that the initial repression was associated with loss of activation-associated histone modifications (H3K9ac, H3K27ac and H3K4me3) and was independent of recruitment of polycomb proteins and deposition of the repressive H3K27me3 modification, which were only observed later in repression. Most remarkable, and in contrast to current models of RBPJ in repression, was the observation that this DNA-binding factor accumulated at the EBNA3C-binding sites only when EBNA3C was functional. Transient reporter assays indicated that repression of these genes was dependent on the interaction between EBNA3C and RBPJ. This was confirmed with a novel EBV-recombinant encoding a mutant of EBNA3C unable to bind RBPJ, by showing this virus was incapable of repressing COBLL1 or ADAM28/ADAMDEC1 in newly infected primary B cells.
References
[1]
Young LS, Rickinson AB. Epstein–Barr virus: 40 years on. Nat Rev Cancer. 2004;4: 757–768. doi: 10.1038/nrc1452. pmid:15510157
[2]
Kutok JL, Wang F. Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol. 2006;1: 375–404. doi: 10.1146/annurev.pathol.1.110304.100209. pmid:18039120
[3]
Davies ML, Xu S, Lyons-Weiler J, Rosendorff A, Webber SA, Wasil LR, et al. Cellular factors associated with latency and spontaneous Epstein-Barr virus reactivation in B-lymphoblastoid cell lines. Virology. 2010;400: 53–67. doi: 10.1016/j.virol.2010.01.002. pmid:20153012
[4]
Touitou R, O'Nions J, Heaney J, Allday MJ. Epstein-Barr virus EBNA3 proteins bind to the C8/alpha7 subunit of the 20S proteasome and are degraded by 20S proteasomes in vitro, but are very stable in latently infected B cells. J Gen Virol. 2005;86: 1269–1277. doi: 10.1099/vir.0.80763–0. pmid:15831937
[5]
Hertle ML, Popp C, Petermann S, Maier S, Kremmer E, Lang R, et al. Differential gene expression patterns of EBV infected EBNA-3A positive and negative human B lymphocytes. PLoS Pathog. 2009;5: e1000506. doi: 10.1371/journal.ppat.1000506. pmid:19578441
[6]
White RE, Kremmer E, Allday MJ. Extensive Co-Operation between the Epstein-Barr Virus EBNA3 Proteins in the Manipulation of Host Gene Expression and Epigenetic Chromatin Modification. Masucci MG, editor. PLoS ONE. 2010;5: e13979. doi: 10.1371/journal.pone.0013979.t001. pmid:21085583
[7]
Zhao B, Mar JC, Maruo S, Lee S, Gewurz BE, Johannsen E, et al. Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines. Proc Natl Acad Sci USA. 2011;108: 337–342. doi: 10.1073/pnas.1017419108. pmid:21173222
[8]
Robertson ES, Grossman S, Johannsen E, Miller C, Lin J, Tomkinson B, et al. Epstein-Barr virus nuclear protein 3C modulates transcription through interaction with the sequence-specific DNA-binding protein J kappa. Journal of Virology. 1995;69: 3108–3116. pmid:7707539
[9]
Robertson ES, Lin J, Kieff E. The amino-terminal domains of Epstein-Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(kappa). Journal of Virology. 1996;70: 3068–3074. pmid:8627785
[10]
Krauer KG, Kienzle N, Young DB, Sculley TB. Epstein-Barr nuclear antigen-3 and -4 interact with RBP-2N, a major isoform of RBP-J kappa in B lymphocytes. Virology. 1996;226: 346–353. doi: 10.1006/viro.1996.0662. pmid:8955054
[11]
Zhao B, Marshall DR, Sample CE. A conserved domain of the Epstein-Barr virus nuclear antigens 3A and 3C binds to a discrete domain of Jkappa. Journal of Virology. 1996;70: 4228–4236. pmid:8676443
[12]
Marshall D, Sample C. Epstein-Barr virus nuclear antigen 3C is a transcriptional regulator. Journal of Virology. 1995;69: 3624–3630. pmid:7745710
Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci. The Company of Biologists Ltd; 2013;126: 2135–2140. doi: 10.1242/jcs.127308. pmid:23729744
[15]
Olave I, Reinberg D, Vales LD. The mammalian transcriptional repressor RBP (CBF1) targets TFIID and TFIIA to prevent activated transcription. Genes Dev. Cold Spring Harbor Laboratory Press; 1998;12: 1621–1637. pmid:9620850 doi: 10.1101/gad.12.11.1621
[16]
Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, et al. A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. Cold Spring Harbor Laboratory Press; 1998;12: 2269–2277. pmid:9694793 doi: 10.1101/gad.12.15.2269
[17]
Hsieh JJ, Zhou S, Chen L, Young DB, Hayward SD. CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci USA. National Academy of Sciences; 1999;96: 23–28. pmid:9874765 doi: 10.1073/pnas.96.1.23
[18]
Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K, Zechner U, et al. SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J. European Molecular Biology Organization; 2002;21: 5417–5426. doi: 10.1093/emboj/cdf549. pmid:12374742
[19]
Oswald F, Winkler M, Cao Y, Astrahantseff K, Bourteele S, Kn？chel W, et al. RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. Mol Cell Biol. American Society for Microbiology; 2005;25: 10379–10390. doi: 10.1128/MCB.25.23.10379–10390.2005. pmid:16287852
[20]
Taniguchi Y, Furukawa T, Tun T, Han H, Honjo T. LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein. Mol Cell Biol. American Society for Microbiology (ASM); 1998;18: 644–654. pmid:9418910 doi: 10.1128/mcb.18.1.644
[21]
Mumm JS, Kopan R. Notch signaling: from the outside in. Dev Biol. 2000;228: 151–165. doi: 10.1006/dbio.2000.9960. pmid:11112321
Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. Annual Reviews 4139 El Camino Way, P.O. Box 10139, Palo Alto, CA 94303–0139, USA; 2003;26: 565–597. doi: 10.1146/annurev.neuro.26.041002.131334. pmid:12730322
[24]
Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, et al. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol. 1995;5: 1416–1423. pmid:8749394 doi: 10.1016/s0960-9822(95)00279-x
[25]
Roehl H, Kimble J. Control of cell fate in C. elegans by a GLP-1 peptide consisting primarily of ankyrin repeats. Nature. Nature Publishing Group; 1993;364: 632–635. doi: 10.1038/364632a0. pmid:8350921
[26]
Kato H, Taniguchi Y, Kurooka H, Minoguchi S, Sakai T, Nomura-Okazaki S, et al. Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development. 1997;124: 4133–4141. pmid:9374409
[27]
Kurooka H, Kuroda K, Honjo T. Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. Nucleic Acids Research. Oxford University Press; 1998;26: 5448–5455. pmid:9826771 doi: 10.1093/nar/26.23.5448
[28]
Petcherski AG, Kimble J. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature. Nature Publishing Group; 2000;405: 364–368. doi: 10.1038/35012645.
[29]
Petcherski AG, Kimble J. Mastermind is a putative activator for Notch. Curr Biol. 2000;10: R471–3. pmid:10898989 doi: 10.1016/s0960-9822(00)00577-7
[30]
Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet. 2000;26: 484–489. doi: 10.1038/82644. pmid:11101851
[31]
Grossman SR, Johannsen E, Tong X, Yalamanchili R, Kieff E. The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the J kappa recombination signal binding protein. Proc Natl Acad Sci USA. 1994;91: 7568–7572. pmid:8052621 doi: 10.1073/pnas.91.16.7568
[32]
Henkel T, Ling PD, Hayward SD, Peterson MG. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science. 1994;265: 92–95. pmid:8016657 doi: 10.1126/science.8016657
[33]
Waltzer L, Logeat F, Brou C, Israel A, Sergeant A, Manet E. The human J kappa recombination signal sequence binding protein (RBP-J kappa) targets the Epstein-Barr virus EBNA2 protein to its DNA responsive elements. EMBO J. European Molecular Biology Organization; 1994;13: 5633–5638. pmid:7988560
[34]
Zimber-Strobl U, Strobl LJ, Meitinger C, Hinrichs R, Sakai T, Furukawa T, et al. Epstein-Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-J kappa, the homologue of Drosophila Suppressor of Hairless. EMBO J. European Molecular Biology Organization; 1994;13: 4973–4982. pmid:7957063
[35]
Zimber-Strobl U, Strobl LJ. EBNA2 and Notch signalling in Epstein-Barr virus mediated immortalization of B lymphocytes. Semin Cancer Biol. 2001;11: 423–434. doi: 10.1006/scbi.2001.0409. pmid:11669604
[36]
Johannsen E, Miller CL, Grossman SR, Kieff E. EBNA-2 and EBNA-3C extensively and mutually exclusively associate with RBPJkappa in Epstein-Barr virus-transformed B lymphocytes. Journal of Virology. American Society for Microbiology (ASM); 1996;70: 4179–4183. pmid:8648764
[37]
Waltzer L, Perricaudet M, Sergeant A, Manet E. Epstein-Barr virus EBNA3A and EBNA3C proteins both repress RBP-J kappa-EBNA2-activated transcription by inhibiting the binding of RBP-J kappa to DNA. Journal of Virology. 1996;70: 5909–5915. pmid:8709211
[38]
Le Roux A, Kerdiles B, Walls D, Dedieu JF, Perricaudet M. The Epstein-Barr virus determined nuclear antigens EBNA-3A, -3B, and -3C repress EBNA-2-mediated transactivation of the viral terminal protein 1 gene promoter. Virology. 1994;205: 596–602. doi: 10.1006/viro.1994.1687. pmid:7975264
[39]
Radkov SA, Bain M, Farrell PJ, West M, Rowe M, Allday MJ. Epstein-Barr virus EBNA3C represses Cp, the major promoter for EBNA expression, but has no effect on the promoter of the cell gene CD21. Journal of Virology. 1997;71: 8552–8562. pmid:9343213
[40]
Maruo S, Wu Y, Ito T, Kanda T, Kieff ED, Takada K. Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth. Proc Natl Acad Sci USA. 2009;106: 4419–4424. doi: 10.1073/pnas.0813134106. pmid:19237563
[41]
Lee S, Sakakibara S, Maruo S, Zhao B, Calderwood MA, Holthaus AM, et al. Epstein-Barr virus nuclear protein 3C domains necessary for lymphoblastoid cell growth: interaction with RBP-Jkappa regulates TCL1. Journal of Virology. American Society for Microbiology; 2009;83: 12368–12377. doi: 10.1128/JVI.01403-09. pmid:19776126
[42]
Calderwood MA, Lee S, Holthaus AM, Blacklow SC, Kieff E, Johannsen E. Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Virology. 2011;414: 19–25. doi: 10.1016/j.virol.2011.02.018. pmid:21440926
[43]
Hayward SD. Viral interactions with the Notch pathway. Semin Cancer Biol. 2004;14: 387–396. doi: 10.1016/j.semcancer.2004.04.018. pmid:15288264
[44]
Hayward SD, Liu J, Fujimuro M. Notch and Wnt signaling: mimicry and manipulation by gamma herpesviruses. Sci STKE. Science Signaling; 2006;2006: re4–re4. doi: 10.1126/stke.3352006re4. pmid:16705130
[45]
Harth-Hertle ML, Scholz BA, Erhard F, Glaser LV, D？lken L, Zimmer R, et al. Inactivation of Intergenic Enhancers by EBNA3A Initiates and Maintains Polycomb Signatures across a Chromatin Domain Encoding CXCL10 and CXCL9. PLoS Pathog. 2013;9: e1003638. doi: 10.1371/journal.ppat.1003638. pmid:24068939
[46]
Bain M, Watson RJ, Farrell PJ, Allday MJ. Epstein-Barr virus nuclear antigen 3C is a powerful repressor of transcription when tethered to DNA. Journal of Virology. 1996;70: 2481–2489. pmid:8642676
[47]
Bourillot PY, Waltzer L, Sergeant A, Manet E. Transcriptional repression by the Epstein-Barr virus EBNA3A protein tethered to DNA does not require RBP-Jkappa. J Gen Virol. 1998;79 (Pt 2): 363–370. pmid:9472621 doi: 10.1099/0022-1317-79-2-363
[48]
Radkov SA, Touitou R, Brehm A, Rowe M, West M, Kouzarides T, et al. Epstein-Barr virus nuclear antigen 3C interacts with histone deacetylase to repress transcription. Journal of Virology. 1999;73: 5688–5697. pmid:10364319
[49]
Knight JS, Lan K, Subramanian C, Robertson ES. Epstein-Barr virus nuclear antigen 3C recruits histone deacetylase activity and associates with the corepressors mSin3A and NCoR in human B-cell lines. Journal of Virology. 2003;77: 4261–4272. pmid:12634383 doi: 10.1128/jvi.77.7.4261-4272.2003
[50]
Touitou R, Hickabottom M, Parker G, Crook T, Allday MJ. Physical and functional interactions between the corepressor CtBP and the Epstein-Barr virus nuclear antigen EBNA3C. Journal of Virology. American Society for Microbiology; 2001;75: 7749–7755. doi: 10.1128/JVI.75.16.7749–7755.2001. pmid:11462050
[51]
McClellan MJ, Khasnis S, Wood CD, Palermo RD, Schlick SN, Kanhere AS, et al. Downregulation of Integrin Receptor-Signaling Genes by Epstein-Barr Virus EBNA 3C via Promoter-Proximal and -Distal Binding Elements. Journal of Virology. 2012;86: 5165–5178. doi: 10.1128/JVI.07161-11. pmid:22357270
[52]
Skalska L, White RE, Parker GA, Sinclair AJ, Paschos K, Allday MJ. Induction of p16(INK4a) is the major barrier to proliferation when Epstein-Barr virus (EBV) transforms primary B cells into lymphoblastoid cell lines. PLoS Pathog. 2013;9: e1003187. doi: 10.1371/journal.ppat.1003187. pmid:23436997
[53]
McClellan MJ, Wood CD, Ojeniyi O, Cooper TJ, Kanhere A, Arvey A, et al. Modulation of enhancer looping and differential gene targeting by epstein-barr virus transcription factors directs cellular reprogramming. PLoS Pathog. 2013;9: e1003636. doi: 10.1371/journal.ppat.1003636. pmid:24068937
[54]
Anderton E, Yee J, Smith P, Crook T, White RE, Allday MJ. Two Epstein–Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma. Oncogene. 2007;27: 421–433. doi: 10.1038/sj.onc.1210668. pmid:17653091
[55]
Skalska L, White RE, Allday MJ. Epigenetic Repression of p16INK4A by Latent Epstein-Barr Virus Requires the Interaction of EBNA3A and EBNA3C with CtBP. Speck SH, editor. PLoS Pathog. 2010;6: e1000951. doi: 10.1371/journal.ppat.1000951.g010. pmid:20548956
[56]
Bazot Q, Paschos K, Skalska L, Kalchschmidt JS, Parker GA, Allday MJ. Epstein-Barr Virus Proteins EBNA3A and EBNA3C Together Induce Expression of the Oncogenic MicroRNA Cluster miR-221/miR-222 and Ablate Expression of Its Target p57KIP2. Flemington EK, editor. PLoS Pathog. Public Library of Science; 2015;11: e1005031. doi: 10.1371/journal.ppat.1005031. pmid:26153983
[57]
Paschos K, Parker GA, Watanatanasup E, White RE, Allday MJ. BIM promoter directly targeted by EBNA3C in polycomb-mediated repression by EBV. Nucleic Acids Research. 2012;40: 7233–7246. doi: 10.1093/nar/gks391. pmid:22584624
[58]
Ben-Bassat H, Goldblum N, Mitrani S, Goldblum T, Yoffey JM, Cohen MM, et al. Establishment in continuous culture of a new type of lymphocyte from a “Burkitt like” malignant lymphoma (line D.G.-75). Int J Cancer. 1977;19: 27–33. pmid:188769 doi: 10.1002/ijc.2910190105
[59]
Allday MJ, Crawford DH, Thomas JA. Epstein-Barr virus (EBV) nuclear antigen 6 induces expression of the EBV latent membrane protein and an activated phenotype in Raji cells. J Gen Virol. 1993;74 (Pt 3): 361–369. pmid:8383171 doi: 10.1099/0022-1317-74-3-361
[60]
Maier S, Santak M, Mantik A, Grabusic K, Kremmer E, Hammerschmidt W, et al. A somatic knockout of CBF1 in a human B-cell line reveals that induction of CD21 and CCR7 by EBNA-2 is strictly CBF1 dependent and that downregulation of immunoglobulin M is partially CBF1 independent. Journal of Virology. American Society for Microbiology; 2005;79: 8784–8792. doi: 10.1128/JVI.79.14.8784–8792.2005. pmid:15994772
[61]
Yatim A, Benne C, Sobhian B, Laurent-Chabalier S, Deas O, Judde J-G, et al. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol Cell. 2012;48: 445–458. doi: 10.1016/j.molcel.2012.08.022. pmid:23022380
[62]
Krejcí A, Bray S. Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes Dev. 2007;21: 1322–1327. doi: 10.1101/gad.424607. pmid:17545467
[63]
Castel D, Mourikis P, Bartels SJJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG. Dynamic binding of RBPJ is determined by Notch signaling status. Genes Dev. Cold Spring Harbor Lab; 2013;27: 1059–1071. doi: 10.1101/gad.211912.112. pmid:23651858
[64]
Portal D, Zhao B, Calderwood MA, Sommermann T, Johannsen E, Kieff E. EBV nuclear antigen EBNALP dismisses transcription repressors NCoR and RBPJ from enhancers and EBNA2 increases NCoR-deficient RBPJ DNA binding. Proc Natl Acad Sci USA. National Acad Sciences; 2011;108: 7808–7813. doi: 10.1073/pnas.1104991108. pmid:21518914
[65]
Messeguer X, Escudero R, Farré D, Nú？ez O, Martínez J, Albà MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18: 333–334. pmid:11847087 doi: 10.1093/bioinformatics/18.2.333
[66]
Farré D, Roset R, Huerta M, Adsuara JE, Roselló L, Albà MM, et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Research. Oxford University Press; 2003;31: 3651–3653. pmid:12824386 doi: 10.1093/nar/gkg605
[67]
Jiang S, Willox B, Zhou H, Holthaus AM, Wang A, Shi TT, et al. Epstein-Barr Virus Nuclear Antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A. Proc Natl Acad Sci USA. 2013. doi: 10.1073/pnas.1321704111.
[68]
Schmidt SCS, Jiang S, Zhou H, Willox B, Holthaus AM, Kharchenko PV, et al. Epstein-Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes. Proc Natl Acad Sci USA. National Acad Sciences; 2014;: 201422580. doi: 10.1073/pnas.1422580112.
[69]
Jin Y, He Z, Liang D, Zhang Q, Zhang H, Deng Q, et al. Carboxyl-terminal amino acids 1052 to 1082 of the latency-associated nuclear antigen (LANA) interact with RBP-Jκ and are responsible for LANA-mediated RTA repression. Journal of Virology. American Society for Microbiology; 2012;86: 4956–4969. doi: 10.1128/JVI.06788-11. pmid:22379075
[70]
Lake RJ, Tsai P-F, Choi I, Won K-J, Fan H-Y. RBPJ, the major transcriptional effector of Notch signaling, remains associated with chromatin throughout mitosis, suggesting a role in mitotic bookmarking. Fortini M, editor. PLoS Genet. Public Library of Science; 2014;10: e1004204. doi: 10.1371/journal.pgen.1004204.
[71]
Haery L, Thompson RC, Gilmore TD. Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy. Genes Cancer. Impact Journals, LLC; 2015;6: 184–213. pmid:26124919 doi: 10.18632/genesandcancer.65
[72]
Iwase S, Lan F, Bayliss P, la Torre-Ubieta de L, Huarte M, Qi HH, et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 2007;128: 1077–1088. doi: 10.1016/j.cell.2007.02.017. pmid:17320160
[73]
Christensen J, Agger K, Cloos PAC, Pasini D, Rose S, Sennels L, et al. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007;128: 1063–1076. doi: 10.1016/j.cell.2007.02.003. pmid:17320161
[74]
Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007;128: 889–900. doi: 10.1016/j.cell.2007.02.013. pmid:17320163
[75]
Lee MG, Norman J, Shilatifard A, Shiekhattar R. Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell. 2007;128: 877–887. doi: 10.1016/j.cell.2007.02.004. pmid:17320162
[76]
Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, et al. The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature. Nature Publishing Group; 2007;447: 601–605. doi: 10.1038/nature05823.
[77]
Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol. Nature Publishing Group; 2012;13: 297–311. doi: 10.1038/nrm3327. pmid:22473470
[78]
Hayakawa T, Ohtani Y, Hayakawa N, Shinmyozu K, Saito M, Ishikawa F, et al. RBP2 is an MRG15 complex component and down-regulates intragenic histone H3 lysine 4 methylation. Genes Cells. Blackwell Publishing Inc; 2007;12: 811–826. doi: 10.1111/j.1365-2443.2007.01089.x.
[79]
Hayakawa T, Nakayama J-I. Physiological roles of class I HDAC complex and histone demethylase. J Biomed Biotechnol. Hindawi Publishing Corporation; 2011;2011: 129383–10. doi: 10.1155/2011/129383. pmid:21049000
[80]
Schoeftner S, Sengupta AK, Kubicek S, Mechtler K, Spahn L, Koseki H, et al. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. EMBO J. EMBO Press; 2006;25: 3110–3122. doi: 10.1038/sj.emboj.7601187. pmid:16763550
[81]
Pasini D, Bracken AP, Hansen JB, Capillo M, Helin K. The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol Cell Biol. American Society for Microbiology; 2007;27: 3769–3779. doi: 10.1128/MCB.01432-06. pmid:17339329
[82]
Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, et al. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell. 2012;148: 664–678. doi: 10.1016/j.cell.2011.12.029. pmid:22325148
[83]
Yu M, Mazor T, Huang H, Huang H-T, Kathrein KL, Woo AJ, et al. Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Mol Cell. 2012;45: 330–343. doi: 10.1016/j.molcel.2011.11.032. pmid:22325351
Cooper S, Dienstbier M, Hassan R, Schermelleh L, Sharif J, Blackledge NP, et al. Targeting polycomb to pericentric heterochromatin in embryonic stem cells reveals a role for H2AK119u1 in PRC2 recruitment. Cell Rep. 2014;7: 1456–1470. doi: 10.1016/j.celrep.2014.04.012. pmid:24857660
Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125: 301–313. doi: 10.1016/j.cell.2006.02.043. pmid:16630818
[88]
Tanay A, O'Donnell AH, Damelin M, Bestor TH. Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci USA. National Acad Sciences; 2007;104: 5521–5526. doi: 10.1073/pnas.0609746104. pmid:17376869
[89]
Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS, et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. van Steensel B, editor. PLoS Genet. Public Library of Science; 2008;4: e1000242. doi: 10.1371/journal.pgen.1000242.
[90]
Mendenhall EM, Koche RP, Truong T, Zhou VW, Issac B, Chi AS, et al. GC-rich sequence elements recruit PRC2 in mammalian ES cells. Madhani HD, editor. PLoS Genet. Public Library of Science; 2010;6: e1001244. doi: 10.1371/journal.pgen.1001244. pmid:21170310
[91]
Lanzuolo C, Roure V, Dekker J, Bantignies F, Orlando V. Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex. Nat Cell Biol. Nature Publishing Group; 2007;9: 1167–1174. doi: 10.1038/ncb1637. pmid:17828248
[92]
Tiwari VK, McGarvey KM, Licchesi JDF, Ohm JE, Herman JG, Schübeler D, et al. PcG proteins, DNA methylation, and gene repression by chromatin looping. Becker PB, editor. PLoS Biol. Public Library of Science; 2008;6: 2911–2927. doi: 10.1371/journal.pbio.0060306. pmid:19053175
[93]
Tiwari VK, Cope L, McGarvey KM, Ohm JE, Baylin SB. A novel 6C assay uncovers Polycomb-mediated higher order chromatin conformations. Genome Res. Cold Spring Harbor Lab; 2008;18: 1171–1179. doi: 10.1101/gr.073452.107. pmid:18502945
[94]
Cheutin T, Cavalli G. Polycomb silencing: from linear chromatin domains to 3D chromosome folding. Curr Opin Genet Dev. 2014;25: 30–37. doi: 10.1016/j.gde.2013.11.016. pmid:24434548
[95]
Zhao B, Zou J, Wang H, Johannsen E, Peng C-W, Quackenbush J, et al. Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proc Natl Acad Sci USA. National Acad Sciences; 2011;108: 14902–14907. doi: 10.1073/pnas.1108892108. pmid:21746931
[96]
Hickabottom M, Parker GA, Freemont P, Crook T, Allday MJ. Two nonconsensus sites in the Epstein-Barr virus oncoprotein EBNA3A cooperate to bind the co-repressor carboxyl-terminal-binding protein (CtBP). J Biol Chem. 2002;277: 47197–47204. doi: 10.1074/jbc.M208116200. pmid:12372828
[97]
Delecluse HJ, Hilsendegen T, Pich D, Zeidler R, Hammerschmidt W. Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci USA. 1998;95: 8245–8250. pmid:9653172 doi: 10.1073/pnas.95.14.8245
[98]
White RE, Calderwood MA, Whitehouse A. Generation and precise modification of a herpesvirus saimiri bacterial artificial chromosome demonstrates that the terminal repeats are required for both virus production and episomal persistence. J Gen Virol. 2003;84: 3393–3403. pmid:14645920 doi: 10.1099/vir.0.19387-0
[99]
Wade-Martins R, Frampton J, James MR. Long-term stability of large insert genomic DNA episomal shuttle vectors in human cells. Nucleic Acids Research. Oxford University Press; 1999;27: 1674–1682. pmid:10075999 doi: 10.1093/nar/27.7.1674
