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Role of the cellular factor CTCF in the regulation of Bovine Leukemia Virus latency and three-dimensional chromatin organization [ChIP-seq]

ABSTRACT: Bovine Leukemia Virus (BLV)-induced tumoral development is a multifactorial phenomenon which remains incompletely understood. Here, we highlight the critical role of the cellular CCCTC-binding factor (CTCF) both in the regulation of BLV transcriptional activities and in the deregulation of the three-dimensional (3D) chromatin architecture surrounding the BLV integration site. We demonstrated the in vivo recruitment of CTCF to three conserved CTCF binding motifs along the BLV provirus. Next, we showed the localization of CTCF to transitions in the histone modifications profile along BLV genome as well as its implication in the repression the 5’Long Terminal Repeat (LTR) promoter activity, thereby contributing to viral latency, while favoring the 3’LTR promoter activity. Finally, we demonstrated that BLV integration deregulated host cellular 3D chromatin organization through the formation of viral/host chromatin loops. Altogether, our results highlight CTCF as a new critical effector of BLV transcriptional regulation and BLV-induced physiopathology.

ORGANISM(S): Ovis aries

PROVIDER: GSE178482 | GEO | 2022/02/18

REPOSITORIES: GEO

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Project description: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).

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Role of the cellular factor CTCF in the regulation of Bovine Leukemia Virus latency and three-dimensional chromatin organization [ChIP-seq]

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