A distinct isoform of lymphoid enhancer binding factor 1 (LEF1) epigenetically restricts EBV reactivation to maintain viral latency
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ABSTRACT:
PROVIDER: PRJNA1028955 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26405600_1.fastq.gz | Fastqsanger.gz | |||
| SRR26405600_2.fastq.gz | Fastqsanger.gz | |||
| SRR26405601_1.fastq.gz | Fastqsanger.gz | |||
| SRR26405601_2.fastq.gz | Fastqsanger.gz | |||
| SRR26405602_1.fastq.gz | Fastqsanger.gz |
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Project description:As a human tumor virus, EBV is present as a latent infection in its associated malignancies where genetic and epigenetic changes have been shown to impede cellular differentiation and viral reactivation. One such change is increased levels of the Wnt signaling effector, lymphoid enhancer binding factor 1 (LEF1) following EBV epithelial infection. In silico analysis of EBV type 1 and 2 genomes identified over 20 Wnt-response elements suggesting that LEF1 may directly bind the EBV genome and regulate the viral life cycle. Using CUT&RUN-seq, LEF1 was shown to bind the latent EBV genome at various sites encoding viral lytic products that included the immediate early transactivator BZLF1 and viral primase BSLF1 genes. SiRNA depletion of specific LEF1 isoforms revealed that the alternative-promoter derived isoform with an N-terminal truncation (∆N LEF1) transcriptionally repressed lytic genes associated with LEF1 binding. Furthermore, forced expression of the ∆N LEF1 isoform antagonized EBV reactivation from latency. The LEF1 mediated repression requires histone deacetylase activity through either recruitment or a direct intrinsic histone deacetylase activity. SiRNA depletion of LEF1 resulted in increased histone 3 lysine 9 and lysine 27 acetylation at LEF1 binding sites and across the EBV genome. These results support a novel role for LEF1 in maintaining EBV latency and restriction viral reactivation via repressive chromatin remodeling of critical lytic cycle factors
2023-12-05 | GSE245534 | GEO
Project description:As a human tumor virus, EBV is present as a latent infection in its associated malignancies where genetic and epigenetic changes have been shown to impede cellular differentiation and viral reactivation. We reported previously that levels of the Wnt signaling effector, lymphoid enhancer binding factor 1 (LEF1) increased following EBV epithelial infection and an epigenetic reprogramming event was maintained even after loss of the viral genome. Elevated LEF1 levels are also observed in nasopharyngeal carcinoma and Burkitt lymphoma. To determine the role played by LEF1 in the EBV life cycle, we used in silico analysis of EBV type 1 and 2 genomes to identify over 20 Wnt-response elements, which suggests that LEF1 may bind directly to the EBV genome and regulate the viral life cycle. Using CUT&RUN-seq, LEF1 was shown to bind the latent EBV genome at various sites encoding viral lytic products that included the immediate early transactivator BZLF1 and viral primase BSLF1 genes. The LEF1 gene encodes various long and short protein isoforms. siRNA depletion of specific LEF1 isoforms revealed that the alternative-promoter derived isoform with an N-terminal truncation (ΔN LEF1) transcriptionally repressed lytic genes associated with LEF1 binding. In addition, forced expression of the ΔN LEF1 isoform antagonized EBV reactivation. As LEF1 repression requires histone deacetylase activity through either recruitment of or direct intrinsic histone deacetylase activity, siRNA depletion of LEF1 resulted in increased histone 3 lysine 9 and lysine 27 acetylation at LEF1 binding sites and across the EBV genome. Taken together, these results indicate a novel role for LEF1 in maintaining EBV latency and restriction viral reactivation via repressive chromatin remodeling of critical lytic cycle factors.
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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 and host gene expression. Epstein-Barr Virus (EBV) is a ubiquitous herpesvirus prevalent in B-cell lymphomas of the immune suppressed. 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, our lab has described a temporal model for immortalization with an initial phase characterized by expression of the Epstein-Barr Nuclear Antigens (EBNAs), high c-Myc activity, and hyper-proliferation 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 the NFkB-activating LMP1, defining latency III. LCLs, however, express a broad distribution of LMP1 such that a subset of these cells expresses LMP1 at levels seen in latency IIb, making it difficult to distinguish these two latency states. In this study, we performed mRNA-Seq on early EBV-infected latency IIb cells and latency III LCLs sorted by NFkB activity. We found that latency IIb transcriptomes clustered independently from latency III independent of NFkB. 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-FISH targeting EBV EBNA2, LMP1, and human CCR7 or MGST1. This study defines latency IIb as a bona fide latency state independent from latency III and identifies biomarkers for understanding EBV-associated tumor heterogeneity
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Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr (EBV) are gammaherpesviruses associated with multiple human malignancies. KSHV is the etiological agent of Kaposi’s Sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). EBV is associated with Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). KSHV and EBV establish life-long latency in the human host with intermittent periods of lytic reactivation. Here, we identified a cellular factor named transforming growth factor-beta regulator 4 (TBRG4) that plays a role in the gammaherpesvirus lifecycle. We find that TBRG4, a protein that is localized to the mitochondria, can regulate lytic reactivation from latency of both KSHV and EBV. Knockdown of TBRG4 in cells latently infected with KSHV or EBV induced viral lytic gene transcription and replication. TBRG4 deficiency causes mitochondrial stress and increases reactive oxygen species (ROS) production. Treatment with a ROS scavenger decreased viral reactivation from latency in TBRG4-depleted cells. These data suggest that TBRG4 serves as a cellular repressor of KSHV and EBV reactivation through the regulation of ROS production. Author summary Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr (EBV) are double-stranded DNA tumor viruses that are associated with multiple cancers in the human population. These include both B and T cell lymphomas, as well as epithelial- and endothelial-derived cancers. Both EBV and KSHV exhibit two phases of their lifecycle, latency and lytic replication. During lytic reactivation, the virus switches from latency and replicates its viral genome to produce new infectious progeny. Here we report that the mitochondrial protein, TBRG4, serves as a cellular repressor of KSHV and EBV lytic reactivation through the regulation of ROS production.
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Project description:Identification of Host Biomarkers of EBV Latency IIb and Latency III
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Project description:Recently global gene expression profiling of patients samples lead to a molecular definition of Burkitt Lymphoma (BL) with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Here we report the discovery of nucleic LEF1 in a very high proportion of BL cases (15/18) and LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression as mantle cell lymphoma (0/5), marginal zone lymphoma (0/6), follicular lymphoma (0/12) or diffuse large B cell lymphoma (DLBCL) (1/31). Using whole genome gene expression profiling after transient knockdown of LEF1 in BL cell lines, new LEF1 target genes were identified. The joint expression of these genes in primary BL samples shows that LEF1 is not only expressed aberrantly in BL but also transcriptionally active. Our study identified aberrantly expressed LEF1 and its target genes suggesting an important functional role in BLs. 3 biological replicates scrb siRNA vs LEF1 si RNA , 4 siRNA are pooled
2013-06-01 | E-GEOD-42637 | biostudies-arrayexpress
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2010-12-31 | E-GEOD-21375 | biostudies-arrayexpress
Project description:Recently global gene expression profiling of patients samples lead to a molecular definition of Burkitt Lymphoma (BL) with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Here we report the discovery of nucleic LEF1 in a very high proportion of BL cases (15/18) and LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression as mantle cell lymphoma (0/5), marginal zone lymphoma (0/6), follicular lymphoma (0/12) or diffuse large B cell lymphoma (DLBCL) (1/31). Using whole genome gene expression profiling after transient knockdown of LEF1 in BL cell lines, new LEF1 target genes were identified. The joint expression of these genes in primary BL samples shows that LEF1 is not only expressed aberrantly in BL but also transcriptionally active. Our study identified aberrantly expressed LEF1 and its target genes suggesting an important functional role in BLs.
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