Implication of the cellular factor CTCF in the regulation of Bovine Leukemia Virus latency and tridimensional chromatin organization

Abstract

Bovine Leukemia Virus (BLV)-induced tumoral development is a multifactorial phenomenon which remains largely unelucidated. Here, we highlighted the critical role of the cellular CCCTC-binding factor (CTCF) both in the regulation of BLV transcriptional activities and in the deregulation of the tridimensional (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 a critical role for CTCF in delimitating the epigenetic landscape along the BLV provirus as well as to repress the 5Long Terminal Repeat (LTR) promoter activity, thereby contributing to viral latency, while favoring the 3LTR promoter activity. Finally, we demonstrated that BLV integration deregulated host cellular 3D chromatin organization through the formation of abnormal viral/host chromatin loops. Altogether, our results highlight CTCF as a new critical effector of BLV transcriptional regulation and BLV-induced physiopathology.