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Antisense transcription of bovine leukemia virus is essential for viral replication and oncogenesis

ABSTRACT: In sheep infected with bovine leukemia virus (BLV), transcription of structural, enzymatic, and accessory genes is silenced. However, the BLV provirus transcribes a series of non-coding RNAs that remain undetected by the host immune response. Specifically, three RNAs (AS1-L, AS1-S, and AS2) are consistently expressed from the antisense strand, originating from transcriptional initiation at the 3'-LTR. To investigate the role of these non-coding RNAs in viral replication and pathogenesis, a reverse genetics approach was devised, capitalizing on a mechanistic disparity in transcription initiation between the 5' and 3' promoters. A two-nucleotide mutation (GG>TA) in the TFIIB-recognition element (BRE) impaired antisense transcription originating from the 3'-LTR. In the context of the provirus, this A1 mutation significantly diminished the expression of antisense RNAs, while not notably affecting sense transcription. When inoculated to sheep, the A1 provirus was infectious but exhibited reduced replication levels, shedding light on the role of antisense transcription in vivo. In comparison to lymphoid organs in sheep infected with a wild-type (WT) provirus, the A1 mutant demonstrated alterations in both the spatial distribution and rates of cell proliferation in the lymph nodes and the spleen. Analysis through RNA sequencing and RT-qPCR unveiled an upregulation of the Hmcn1 gene in B-lymphocytes from A1-infected sheep. Further examination via confocal microscopy and immunohistochemistry revealed an increase in the amount of hemicentin-1 protein encoded by Hmcn1 in peripheral blood mononuclear cells (PBMCs) and lymphoid organs of sheep infected with the A1 mutant. RNA interference targeting Hmcn1 expression impacted the migration of ovine kidney (OVK) cells in vitro. In contrast to the WT provirus, the A1 mutant lacked oncogenic activity when inoculated into sheep. Collectively, this study underscores the essential role of antisense transcription in BLV replication and pathogenicity. These findings may offer valuable insights into understanding the relevance of antisense transcription in the context of human T-cell leukemia virus (HTLV-1).

ORGANISM(S): Ovis aries

PROVIDER: GSE255715 | GEO | 2024/02/17

REPOSITORIES: GEO

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Project description:LlorénsRico2016 - Effects of cis-Encoded antisense RNAs (asRNAs) - Case1 Three putative effects of the asRNAs were considered in this study: in case 1 (this model) , the binding of the asRNA to the corresponding mRNA induces degradation of the duplex. In case 2, the binding of the asRNA to the mRNA induces degradation of the mRNA, but not of the asRNA. In case 3, the mRNA and the asRNA bind reversibly to form a stable duplex, preventing translation of the mRNA. In all the three cases, binding to the ribosome protects the mRNA from the effect of the asRNA. This model is described in the article: Bacterial antisense RNAs are mainly the product of transcriptional noise. Lloréns-Rico V, Cano J, Kamminga T, Gil R, Latorre A, Chen WH, Bork P, Glass JI, Serrano L, Lluch-Senar M. Sci Adv 2016 Mar; 2(3): e1501363 Abstract: cis-Encoded antisense RNAs (asRNAs) are widespread along bacterial transcriptomes. However, the role of most of these RNAs remains unknown, and there is an ongoing discussion as to what extent these transcripts are the result of transcriptional noise. We show, by comparative transcriptomics of 20 bacterial species and one chloroplast, that the number of asRNAs is exponentially dependent on the genomic AT content and that expression of asRNA at low levels exerts little impact in terms of energy consumption. A transcription model simulating mRNA and asRNA production indicates that the asRNA regulatory effect is only observed above certain expression thresholds, substantially higher than physiological transcript levels. These predictions were verified experimentally by overexpressing nine different asRNAs in Mycoplasma pneumoniae. Our results suggest that most of the antisense transcripts found in bacteria are the consequence of transcriptional noise, arising at spurious promoters throughout the genome. This model is hosted on BioModels Database and identified by: MODEL1511170000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:LlorénsRico2016 - Effects of cis-Encoded antisense RNAs (asRNAs) - Case3 Three putative effects of the asRNAs were considered in this study: in case 1, the binding of the asRNA to the corresponding mRNA induces degradation of the duplex. In case 2, the binding of the asRNA to the mRNA induces degradation of the mRNA, but not of the asRNA. In case 3 (this model), the mRNA and the asRNA bind reversibly to form a stable duplex, preventing translation of the mRNA. In all the three cases, binding to the ribosome protects the mRNA from the effect of the asRNA. This model is described in the article: Bacterial antisense RNAs are mainly the product of transcriptional noise. Lloréns-Rico V, Cano J, Kamminga T, Gil R, Latorre A, Chen WH, Bork P, Glass JI, Serrano L, Lluch-Senar M. Sci Adv 2016 Mar; 2(3): e1501363 Abstract: cis-Encoded antisense RNAs (asRNAs) are widespread along bacterial transcriptomes. However, the role of most of these RNAs remains unknown, and there is an ongoing discussion as to what extent these transcripts are the result of transcriptional noise. We show, by comparative transcriptomics of 20 bacterial species and one chloroplast, that the number of asRNAs is exponentially dependent on the genomic AT content and that expression of asRNA at low levels exerts little impact in terms of energy consumption. A transcription model simulating mRNA and asRNA production indicates that the asRNA regulatory effect is only observed above certain expression thresholds, substantially higher than physiological transcript levels. These predictions were verified experimentally by overexpressing nine different asRNAs in Mycoplasma pneumoniae. Our results suggest that most of the antisense transcripts found in bacteria are the consequence of transcriptional noise, arising at spurious promoters throughout the genome. This model is hosted on BioModels Database and identified by: MODEL1511170002. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Antisense transcription of bovine leukemia virus is essential for viral replication and oncogenesis

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