title: Epigenetic regulation of the latency-associated region of Marek's disease virus in tumor-derived T-cell lines and primary lymphoma.
abstract: Meq is the major Marek's disease virus (MDV)-encoded oncoprotein and is essential for T-cell lymphomagenesis. Meq and several noncoding RNAs, including three microRNA (MiR) clusters, are expressed from the repeats of the MDV genome during latent infection of T cells. To investigate the state of the chromatin in this and flanking regions, we carried out chromatin immunoprecipitation (ChIP) analysis of covalent histone modifications and associated bound proteins. T-cell lines and a lymphoma were compared. The chromatin around the promoters for Meq and the noncoding RNAs in both cell lines and the lymphoma were associated with H3K9 acetylation and H3K4 trimethylation, which are marks of transcriptionally active chromatin. These correlated with bound Meq-c-Jun heterodimers. The only binding site for Meq homodimers is located at the lytic origin of replication (OriLyt), next to the lytic gene pp38. This region lacked active marks and was associated with repressive histone modifications (H3K27 and H3K9 trimethylation). DNA CpG methylation was investigated using methylated DNA precipitation (MeDP). In cell lines, DNA methylation was abundant across the repeats but noticeably reduced or absent around the active promoters. In primary tumors, CpG methylation occurred less than 2 months after infection, focused within the ICP4 gene. These data suggest that nonrandom de novo DNA methylation occurs early in lymphomagenesis. In addition, the histone data indicate a role for Meq in the epigenetic regulation of the MDV genome repeats in transformed T cells and suggest that the OriLyt region and the Meq/MiR region might be separated by chromatin boundary elements, and preliminary data on CTCF binding are consistent with this.
authors.affiliation: Section of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Brown
authors.forename: Venugopal
authors.initials: V
authors.lastname: Nair
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Allday
mesh_terms: D000818:Animals; D001483:Base Sequence; D001717:Birds; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation; D017931:DNA Primers; D044127:Epigenesis, Genetic; D006801:Humans; D008223:Lymphoma / Q000473:pathology / Q000821:virology*; D025922:Mardivirus / Q000235:genetics* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000821:virology*; D017735:Virus Latency / Q000235:genetics*
chemical_list: D017931:DNA Primers
references.citation: J Virol. 2001 Aug;75(16):7749-55
references.pmid: 11462050
references.citation: PLoS Pathog. 2009 Jun;5(6):e1000492
references.pmid: 19557159
references.citation: Avian Dis. 1977 Jan-Mar;21(1):69-76
references.pmid: 190995
references.citation: J Virol. 1994 Oct;68(10):6280-90
references.pmid: 8083968
references.citation: Virology. 1994 May 15;201(1):132-6
references.pmid: 8178477
references.citation: Genes Dev. 2006 Sep 1;20(17):2349-54
references.pmid: 16951251
references.citation: Bioessays. 2010 Jan;32(1):37-50
references.pmid: 20020479
references.citation: J Gen Virol. 1997 Sep;78 ( Pt 9):2191-8
references.pmid: 9292006
references.citation: Cell. 2008 Feb 8;132(3):422-33
references.pmid: 18237772
references.citation: Mol Cell Biol. 1999 Jan;19(1):777-87
references.pmid: 9858600
references.citation: Nature. 2003 Apr 17;422(6933):735-8
references.pmid: 12700765
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1687-92
references.pmid: 16446447
references.citation: PLoS Pathog. 2010 Jun 03;6(6):e1000935
references.pmid: 20532208
references.citation: Cell. 2009 Jun 26;137(7):1194-211
references.pmid: 19563753
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10):7054-9
references.pmid: 11997455
references.citation: EMBO Rep. 2009 Nov;10(11):1213-9
references.pmid: 19834511
references.citation: J Virol. 2004 May;78(9):4753-60
references.pmid: 15078957
references.citation: Trends Microbiol. 2010 Oct;18(10):439-47
references.pmid: 20724161
references.citation: Virus Genes. 2007 Dec;35(3):643-50
references.pmid: 17619133
references.citation: J Exp Med. 2011 Mar 14;208(3):605-15
references.pmid: 21383055
references.citation: Philos Trans R Soc Lond B Biol Sci. 1997 Dec 29;352(1364):1951-62
references.pmid: 9451743
references.citation: Virus Genes. 2000;21(1-2):51-64
references.pmid: 11022789
references.citation: J Gen Virol. 1994 Jul;75 ( Pt 7):1713-22
references.pmid: 8021600
references.citation: J Virol. 2006 Sep;80(17):8778-86
references.pmid: 16912324
references.citation: J Virol. 2009 Nov;83(21):11142-51
references.pmid: 19692466
references.citation: J Virol. 1998 Jan;72(1):388-95
references.pmid: 9420237
references.citation: Dev Biol (Basel). 2004;119:147-54
references.pmid: 15742626
references.citation: Poult Sci. 2003 Jun;82(6):893-8
references.pmid: 12817443
references.citation: Cell. 2006 Apr 21;125(2):315-26
references.pmid: 16630819
references.citation: Acta Virol. 1999 Apr-Jun;43(2-3):113-20
references.pmid: 10696430
references.citation: J Virol. 2006 Feb;80(3):1160-6
references.pmid: 16414993
references.citation: PLoS Pathog. 2011 Feb;7(2):e1001305
references.pmid: 21383974
references.citation: Nat Genet. 2007 Feb;39(2):232-6
references.pmid: 17200670
references.citation: J Virol. 1992 Jan;66(1):85-94
references.pmid: 1309266
references.citation: Genes Dev. 2000 Jul 1;14(13):1553-77
references.pmid: 10887150
references.citation: J Virol. 1997 Feb;71(2):1353-61
references.pmid: 8995659
references.citation: EMBO J. 1993 Aug;12(8):3277-86
references.pmid: 8393785
references.citation: J Virol. 1993 Jan;67(1):82-92
references.pmid: 8380099
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6621-5
references.pmid: 10359761
references.citation: J Exp Med. 2006 May 15;203(5):1307-17
references.pmid: 16651385
references.citation: Virology. 1992 Aug;189(2):657-67
references.pmid: 1322594
references.citation: Res Vet Sci. 2000 Aug;69(1):17-23
references.pmid: 10924389
references.citation: J Virol. 2005 Apr;79(7):4545-9
references.pmid: 15767457
references.citation: J Virol. 1996 Oct;70(10):7161-70
references.pmid: 8794363
references.citation: Biochim Biophys Acta. 2010 Mar-Apr;1799(3-4):246-56
references.pmid: 20045093
references.citation: J Virol. 1995 Jul;69(7):4037-44
references.pmid: 7769661
references.citation: J Virol. 2001 Jun;75(11):5159-73
references.pmid: 11333897
references.citation: J Virol. 2003 May;77(10):5985-96
references.pmid: 12719590
references.citation: J Virol. 2007 Jul;81(13):7164-70
references.pmid: 17459919
references.citation: J Virol. 2003 Dec;77(23):12841-51
references.pmid: 14610205
references.citation: J Virol. 2009 Jan;83(2):859-69
references.pmid: 18971275
references.citation: Nat Rev Genet. 2011 Feb;12(2):123-35
references.pmid: 21221116
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11815-20
references.pmid: 15289599
references.citation: PLoS Pathog. 2010 Jul 22;6(7):e1001013
references.pmid: 20661424
references.citation: Philos Trans R Soc Lond B Biol Sci. 2001 Apr 29;356(1408):413-20
references.pmid: 11313002
references.citation: Virology. 2010 Apr 10;399(2):312-21
references.pmid: 20137800
references.citation: Acta Virol. 1999 Apr-Jun;43(2-3):94-101
references.pmid: 10696427