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See detailIdentification and characterization of novel bovine leukemia virus (BLV) antisense transcripts in leukemic and pre-leukemic clones
Durkin, Keith ULg; Rosewick, Nicolas; Artesi, Maria ULg et al

Conference (2016, May 21)

The deltaretrovirus Bovine Leukemia Virus (BLV) is closely related to the Human T-cell leukemia virus-1 (HTLV-1). Cattle are the natural host of BLV where it integrates into B-cells, produces a lifelong ... [more ▼]

The deltaretrovirus Bovine Leukemia Virus (BLV) is closely related to the Human T-cell leukemia virus-1 (HTLV-1). Cattle are the natural host of BLV where it integrates into B-cells, produces a lifelong infection. Most infected animals remain asymptomatic but following a protracted latency period about ~5% develop an aggressive leukemia/lymphoma, mirroring the disease trajectory of HTLV-1. Like the case in HTLV-1 the 5’LTR BLV provirus is transcriptionally silent in tumors, however the provirus is not entirely quiescent, constitutively express the BLV microRNAs in tumors. Using RNA-seq, we found that in addition to microRNAs, the BLV provirus also constitutively expresses two antisense transcripts in all BLV infected samples examined. The first transcript (AS1) has alternate potential polyadenylation sites generating a short transcript of ~600bp (AS1-S) and a less abundant longer transcript of ~2200bp (AS1-L). Alternative splicing also creates a second transcript of ~400bp (AS2) utilizing the first exon of AS1. Production of AS transcripts from the 3’LTR was supported by reporter assays demonstrating that the BLV LTR has substantial and Tax-independent antisense promoter activity. BLV AS transcripts predominantly localize in the nucleus. Examination of protein coding potential showed AS2 to be non-coding, while the AS1-S/L transcripts coding potential is ambiguous, with a small potential open reading frame (ORF) of 264bp present. The AS1-L transcript overlaps the BLV microRNAs transcribed in the sense direction. Using high throughput sequencing of RNA-ligase-mediated (RLM) 5' RACE products, we show that the perfect complementary between the transcripts leads to RNA-induced silencing complex (RISC) mediated cleavage of AS1-L. Furthermore, experiments using BLV proviruses where the microRNAs were removed or inverted point to additional transcriptional interactions between the two viral RNA species. Knock down of AS1-S/L using locked nucleic acids (LNAs) showed no obvious effect on the cells phenotype. While a detailed elucidation of the BLV antisense transcripts function remains in the future, the constitutive expression in all samples examined, points to a vital role for the transcripts in the life cycle and oncogenic potential of BLV. [less ▲]

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See detailCharacterization of novel Bovine Leukemia Virus (BLV) antisense transcripts by deep sequencing reveals constitutive expression in tumors and transcriptional interaction with viral microRNAs.
Durkin, Keith ULg; Rosewick, Nicolas; Artesi, Maria ULg et al

in Retrovirology (2016), 13(1), 33

BACKGROUND: Bovine Leukemia Virus (BLV) is a deltaretrovirus closely related to the Human T cell leukemia virus-1 (HTLV-1). Cattle are the natural host of BLV where it integrates into B-cells, producing a ... [more ▼]

BACKGROUND: Bovine Leukemia Virus (BLV) is a deltaretrovirus closely related to the Human T cell leukemia virus-1 (HTLV-1). Cattle are the natural host of BLV where it integrates into B-cells, producing a lifelong infection. Most infected animals remain asymptomatic but following a protracted latency period about 5 % develop an aggressive leukemia/lymphoma, mirroring the disease trajectory of HTLV-1. The mechanisms by which these viruses provoke cellular transformation remain opaque. In both viruses little or no transcription is observed from the 5'LTR in tumors, however the proviruses are not transcriptionally silent. In the case of BLV a cluster of RNA polymerase III transcribed microRNAs are highly expressed, while the HTLV-1 antisense transcript HBZ is consistently found in all tumors examined. RESULTS: Here, using RNA-seq, we demonstrate that the BLV provirus also constitutively expresses antisense transcripts in all leukemic and asymptomatic samples examined. The first transcript (AS1) can be alternately polyadenylated, generating a transcript of ~600 bp (AS1-S) and a less abundant transcript of ~2200 bp (AS1-L). Alternative splicing creates a second transcript of ~400 bp (AS2). The coding potential of AS1-S/L is ambiguous, with a small open reading frame of 264 bp, however the transcripts are primarily retained in the nucleus, hinting at a lncRNA-like role. The AS1-L transcript overlaps the BLV microRNAs and using high throughput sequencing of RNA-ligase-mediated (RLM) 5'RACE, we show that the RNA-induced silencing complex (RISC) cleaves AS1-L. Furthermore, experiments using altered BLV proviruses with the microRNAs either deleted or inverted point to additional transcriptional interference between the two viral RNA species. CONCLUSIONS: The identification of novel viral antisense transcripts shows the BLV provirus to be far from silent in tumors. Furthermore, the consistent expression of these transcripts in both leukemic and nonmalignant clones points to a vital role in the life cycle of the virus and its tumorigenic potential. Additionally, the cleavage of the AS1-L transcript by the BLV encoded microRNAs and the transcriptional interference between the two viral RNA species suggest a shared role in the regulation of BLV. [less ▲]

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See detailHTLV-1/BLV antisense-RNA dependent host gene perturbation in pre-leukemic and leukemic clones
Rosewick, Nicolas; Durkin, Keith ULg; Marçais, Ambroise et al

in Retrovirology (2015, August 28), 12(1),

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See detailImproving the methodology for the detection of proviral integration sites in the host genome via high throughput sequencing.
Durkin, Keith ULg; Artesi, Maria ULg; Rosewick, Nicolas et al

in Retrovirology (2015, August 28), 12(1),

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See detailImproving proviral integration site detection with high throughput sequencing
Durkin, Keith ULg; Artesi, Maria ULg; Rosewick, Nicolas et al

Poster (2015, May)

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See detailExploring the Deltaretrovirus Tumor Transcriptome: Lessons from RNA-Seq
Rosewick, Nicolas; Durkin, Keith ULg; Thys, Wannes et al

Conference (2014, June)

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See detailIdentification of two noncoding antisense transcripts in BLV and their interaction with the BLV encoded miRNAs
Durkin, Keith ULg; Rosewick, Nicolas; Momont, Mélanie et al

Conference (2014, June)

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See detailIdentification of two antisense transcripts in BLV and their interaction with BLV-encoded microRNAs.
Durkin, Keith ULg; Rosewick, Nicolas; Momont, Mélanie et al

Poster (2014, February)

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See detailElucidating the role of Bovine Leukemia Virus encoded micro-RNAs
Durkin, Keith ULg; Rosewick, Nicolas; Momont, Momont et al

in Retrovirology (2014, January 07), 11(1), 62

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See detailDeep sequencing reveals abundant non-canonical retroviral microRNAs in B-cell leukemia/lymphoma
Rosewick, Nicolas; Momont, Mélanie ULg; Durkin, Keith ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy however remains poorly understood, especially as viral ... [more ▼]

Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy however remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the Bovine Leukemia Virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of non-canonical Pol IIItranscribed viral microRNAs in leukemic B-cells in the complete absence of Pol II 5’ LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, BLV microRNAs represent ~ 40 % of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. BLV microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute in deciphering the intricate perturbations that underlie malignant transformation. [less ▲]

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See detailViral expression in bovine leukemia virus-induced tumor cells.
Van Den Broeke, Anne; Cleuter, Yvette; Portetelle, Daniel ULg et al

in Developments in Biological Standardization (1990), 72

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See detailEven transcriptionally competent proviruses are silent in bovine leukemia virus-induced sheep tumor cells.
Van Den Broeke, Anne; Cleuter, Yvette; Chen, G. et al

in Modern trends in human leukemia VIII (R. Neth., ed.), Springer Verlag, Berlin (1989)

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