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Landscape of the EBV-Host chromatin interactome and gene regulation

ABSTRACT: The three-dimensional (3D) chromatin structure of Epstein-Barr Virus (EBV) within host cells and the underlying mechanisms of chromatin interaction and gene regulation, particularly those involving EBV’s non-coding RNAs (ncRNAs), have remained largely unknown. In this study, we employed state-of-the-art techniques of 3D genome mapping and super-resolution microscopy to delineate the spatial architecture of EBV in human lymphoblastoid cells. We discovered that EBV utilizes host CCCTC binding factor (CTCF) and RNA polymerase II (RNAPII) proteins to form distinct chromatin contact domains (CCDs) and RNAPII-associated interaction domains (RAIDs). These domains’ anchors serve as platforms for extensive interactions with host chromatin, modulating host gene expression. Notably, EBV ncRNAs target and contact with less accessible regions of host chromatin, especially EBERs with the cofactor nucleolin (NCL), to repress genes via the inhibition of RNAPII-associated chromatin loops. This mechanism governs genes crucial for host infection control, immune response, and cell cycle regulation. Our findings provide new insights into the sophisticated interplay between EBV and host chromatin, unveiling novel regulatory mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281522 | GEO | 2025/04/06

REPOSITORIES: GEO

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Project description:Epstein-Barr virus (EBV) establishes life-long latency in human B-cells by maintaining its chromatinized episomes within the nucleus. These circularized mini-chromosomes do not integrate into the host genome. Therefore, it is essential for EBV to organize its chromatin in a manner suitable for genomic stability, DNA replication, and efficient gene expression. Poly [ADP-ribose] polymerase 1 (PARP1) activity is significantly higher in B-cells infected with EBV than those without, and considerably higher in the transcriptionally active type III latency compared to the immunoevasive type I. In addition to its role in DNA damage response, PARP1 has been implicated in transcriptional regulation and structural maintenance of both the human and EBV genome at specific regions. To better understand PARP1's role in the regulation of the EBV episome, we have functionally characterized the effect of PARP enzymatic inhibition on total episomal structure through in situ Hi-C mapping, generating the first complete 3D structure of the EBV genome. We have also mapped intragenomic contact changes after PARP inhibition to global binding of the chromatin looping factors CTCF and cohesin across the EBV genome. Additionally, PARP inhibition was shown to alter gene expression at the regions where chromatin looping was most effected. Finally, we have identified a novel function of PARP, which regulates cohesin complex chromatin binding. In conclusion, PARP1 inhibition does not alter the location of cohesin binding but does increase its frequency of binding at these regions. Despite this, there are fewer overall unique intragenomic interactions after PARP inhibition, while some areas have new chromatin loops not seen in the untreated EBV episome, leading us to conclude that PARP does have an essential role in the regulation of global EBV chromatin structure. The altered expression profile after the structural rearrangement induced by PARP inhibition also supports the idea that PARP1 helps maintain EBV latency programs.

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Landscape of the EBV-Host chromatin interactome and gene regulation

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