KSHV PAN RNA Associates with Demethylases UTX and JMJD3 to Activate Lytic Replication through a Physical Interaction with the Virus Genome

被引:119
作者
Rossetto, Cyprian C. [1 ]
Pari, Gregory [1 ]
机构
[1] Univ Nevada, Reno Sch Med, Dept Microbiol & Immunol, Reno, NV 89557 USA
来源
PLOS PATHOGENS | 2012年 / 8卷 / 05期
关键词
SARCOMA-ASSOCIATED HERPESVIRUS; LONG NONCODING RNA; POLYADENYLATED NUCLEAR-RNA; GENE-EXPRESSION; SWITCH PROTEIN; VIRAL GENOME; CHROMATIN; BINDING; GROWTH; RTA;
D O I
10.1371/journal.ppat.1002680
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma and body cavity lymphomas. KSHV lytic infection produces PAN RNA, a highly abundant noncoding polyadenylated transcript that is retained in the nucleus. We recently demonstrated that PAN RNA interacts with several viral and cellular factors and can disregulate the expression of genes that modulate immune response. In an effort to define the role of PAN RNA in the context of the virus genome we generated a recombinant BACmid that deleted the PAN RNA locus. Because of the apparent duplication of the PAN RNA locus in BAC36, we generated BAC36CR, a recombinant BACmid that removes the duplicated region. BAC36CR was used as a template to delete most of the PAN RNA locus to generate BAC36CR Delta PAN. BAC36CR Delta PAN failed to produce supernatant virus and displayed a general decrease in mRNA accumulation of representative immediate early, early and late genes. Most strikingly, K-Rta expression was decreased in lytically induced BAC36CR Delta PAN-containing cell lines at early and late time points post induction. Expression of PAN RNA in trans in BAC36CR Delta PAN containing cells resulted in an increase in K-Rta expression, however K-Rta over expression failed to rescue BAC36CR Delta PAN, suggesting that PAN RNA plays a wider role in virus replication. To investigate the role of PAN RNA in the activation of K-Rta expression, we demonstrate that PAN RNA physically interacts with the ORF50 promoter. RNA chromatin immunoprecipitation assays show that PAN RNA interacts with demethylases JMJD3 and UTX, and the histone methyltransferase MLL2. Consistent with the interaction with demethylases, expression of PAN RNA results in a decrease of the repressive H3K27me3 mark at the ORF50 promoter. These data support a model where PAN RNA is a multifunctional regulatory transcript that controls KSHV gene expression by mediating the modification of chromatin by targeting the KSHV repressed genome.
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页数:15
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共 38 条
[1]   UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development [J].
Agger, Karl ;
Cloos, Paul A. C. ;
Christensen, Jesper ;
Pasini, Diego ;
Rose, Simon ;
Rappsilber, Juri ;
Issaeva, Irina ;
Canaani, Eli ;
Salcini, Anna Elisabetta ;
Helin, Kristian .
NATURE, 2007, 449 (7163) :731-U10
[2]  
Al-Maghrabi JA, 2011, SAUDI MED J, V32, P451
[3]   A Viral Nuclear Noncoding RNA Binds Re-localized Poly(A) Binding Protein and Is Required for Late KSHV Gene Expression [J].
Borah, Sumit ;
Darricarrere, Nicole ;
Darnell, Alicia ;
Myoung, Jinjong ;
Steitz, Joan A. .
PLOS PATHOGENS, 2011, 7 (10)
[4]   Identification of Direct Transcriptional Targets of the Kaposi's Sarcoma-Associated Herpesvirus Rta Lytic Switch Protein by Conditional Nuclear Localization [J].
Bu, Wei ;
Palmeri, Diana ;
Krishnan, Raghu ;
Marin, Roxana ;
Aris, Virginie M. ;
Soteropoulos, Patricia ;
Lukac, David M. .
JOURNAL OF VIROLOGY, 2008, 82 (21) :10709-10723
[5]   Two subclasses of Kaposi's sarcoma-associated herpesvirus lytic cycle promoters distinguished by open reading frame 50 mutant proteins that are deficient in binding to DNA [J].
Chang, PJ ;
Shedd, D ;
Miller, G .
JOURNAL OF VIROLOGY, 2005, 79 (14) :8750-8763
[6]   Open reading frame 50 protein of Kaposi's sarcoma-associated herpesvirus directly activates the viral PAN and K12 genes by binding to related response elements [J].
Chang, PJ ;
Shedd, D ;
Gradoville, L ;
Cho, MS ;
Chen, LW ;
Chang, J ;
Miller, G .
JOURNAL OF VIROLOGY, 2002, 76 (07) :3168-3178
[7]   Genome-wide identification of binding sites for Kaposi's sarcoma-associated herpesvirus lytic switch protein, RTA [J].
Chen, Jiguo ;
Ye, Fengchun ;
Xie, Jianping ;
Kuhne, Kurt ;
Gao, Shou-Jiang .
VIROLOGY, 2009, 386 (02) :290-302
[8]   Genomic Maps of Long Noncoding RNA Occupancy Reveal Principles of RNA-Chromatin Interactions [J].
Chu, Ci ;
Qu, Kun ;
Zhong, Franklin L. ;
Artandi, Steven E. ;
Chang, Howard Y. .
MOLECULAR CELL, 2011, 44 (04) :667-678
[9]   A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response [J].
Huarte, Maite ;
Guttman, Mitchell ;
Feldser, David ;
Garber, Manuel ;
Koziol, Magdalena J. ;
Kenzelmann-Broz, Daniela ;
Khalil, Ahmad M. ;
Zuk, Or ;
Amit, Ido ;
Rabani, Michal ;
Attardi, Laura D. ;
Regev, Aviv ;
Lander, Eric S. ;
Jacks, Tyler ;
Rinn, John L. .
CELL, 2010, 142 (03) :409-419
[10]   Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth [J].
Issaeva, Irina ;
Zonis, Yulia ;
Rozovskaia, Tanya ;
Orlovsky, Kira ;
Croce, Carlo M. ;
Nakamura, Tatsuya ;
Mazo, Alex ;
Eisenbach, Lea ;
Canaani, Eli .
MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (05) :1889-1903