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Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication.

ABSTRACT: Epstein-Barr virus (EBV) microRNAs miR-BHRF1-1, -2, and -3 have been detected in latency III-infected lymphoblasts, where they are encoded within EBNA transcripts (X. Cai, A. Schafer, S. Lu, J. P. Bilello, R. C. Desrosiers, R. Edwards, N. Raab-Traub, and B. R. Cullen, PLoS Pathog. 2:e23, 2006). In latency III-infected lymphoblasts, we have also identified a stable 1.3-kb RNA, which begins 3' to miR-BHRF1-1, includes the BHRF1 open reading frame, and ends near miR-BHRF1-2. This 1.3-kb RNA is the residue of Drosha cleavage of the BHRF1 microRNAs from EBNA transcripts. Early after induction of EBV replication in latency I-infected Akata lymphoblasts, BHRF1 spliced 1.4-kb mRNA accumulated along with low levels of miR-BHRF1-2 and -3 and a 0.9-kb Drosha or miR-BHRF1-2 cleavage product of BHRF1 mRNA. The turning on of latency III infection at 48 to 72 h after induction of EBV replication was associated with higher miR-BHRF1-1, -2, and -3 levels; accumulation of the 1.3-kb RNA residue in the nucleus; abundant BHRF1 spliced 1.4-kb mRNA in the cytoplasm; and more abundant 0.9-kb mRNA cleavage product in the cytoplasm. These findings implicate miR-BHRF1-2 in 3' cleavage of BHRF1 mRNA in the cytoplasm and Drosha in cleavage of latency III EBNA and EBV replication-associated BHRF1 transcripts in the nucleus.

SUBMITTER: Xing L

PROVIDER: S-EPMC2045418 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication.

Xing Li L Kieff Elliott E

Journal of virology 20070711 18

Epstein-Barr virus (EBV) microRNAs miR-BHRF1-1, -2, and -3 have been detected in latency III-infected lymphoblasts, where they are encoded within EBNA transcripts (X. Cai, A. Schafer, S. Lu, J. P. Bilello, R. C. Desrosiers, R. Edwards, N. Raab-Traub, and B. R. Cullen, PLoS Pathog. 2:e23, 2006). In latency III-infected lymphoblasts, we have also identified a stable 1.3-kb RNA, which begins 3' to miR-BHRF1-1, includes the BHRF1 open reading frame, and ends near miR-BHRF1-2. This 1.3-kb RNA is the ...[more]

PMID: 17626073

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Project description:Deciphering the molecular pathogenesis of virally induced cancers is challenging due, in part, to the heterogeneity of both viral gene expression and host gene expression. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus prevalent in B-cell lymphomas of immune-suppressed individuals. EBV infection of primary human B cells leads to their immortalization into lymphoblastoid cell lines (LCLs), serving as a model of these lymphomas. In previous studies, reports from our laboratory have described a temporal model for immortalization with an initial phase characterized by expression of Epstein-Barr nuclear antigens (EBNAs), high levels of c-Myc activity, and hyperproliferation in the absence of the latent membrane proteins (LMPs), called latency IIb. This is followed by the long-term outgrowth of LCLs expressing the EBNAs along with the LMPs, particularly NFκB-activating LMP1, defining latency III. However, LCLs express a broad distribution of LMP1 such that a subset of these cells express LMP1 at levels similar to those seen in latency IIb, making it difficult to distinguish these two latency states. In this study, we performed mRNA sequencing (mRNA-Seq) on early EBV-infected latency IIb cells and latency III LCLs sorted by NFκB activity. We found that latency IIb transcriptomes clustered independently from latency III independently of NFκB. We identified and validated mRNAs defining these latency states. Indeed, we were able to distinguish latency IIb cells from LCLs expressing low levels of LMP1 using multiplex RNA-fluorescence in situ hybridization (RNA-FISH) targeting EBV EBNA2 or LMP1 and human CCR7 or MGST1 This report defines latency IIb as a bona fide latency state independent from latency III and identifies biomarkers for understanding EBV-associated tumor heterogeneity.IMPORTANCE EBV is a ubiquitous pathogen, with >95% of adults harboring a life-long latent infection in memory B cells. In immunocompromised individuals, latent EBV infection can result in lymphoma. The established expression profile of these lymphomas is latency III, which includes expression of all latency genes. However, single-cell analysis of EBV latent gene expression in these lymphomas suggests heterogeneity where most cells express the transcription factor, EBNA2, and only a fraction of the cells express membrane protein LMP1. Our work describes an early phase after infection where the EBNAs are expressed without LMP1, called latency IIb. However, LMP1 levels within latency III vary widely, making these states hard to discriminate. This may have important implications for therapeutic responses. It is crucial to distinguish these states to understand the molecular pathogenesis of these lymphomas. Ultimately, better tools to understand the heterogeneity of these cancers will support more-efficacious therapies in the future.

Dataset Information

Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication.

Publications

Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication.

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