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Epstein-Barr Virus episome physically interacts with active regions of the host genome in lymphoblastoid cells

ABSTRACT: Epstein-Barr virus (EBV) episome is known to interact with the three-dimensional structure of human genome in infected cells. However, the exact locations of these interactions and their potential functional consequences remain unclear. Recently the high-resolution chromatin interaction capture (Hi-C) assays in lymphoblastoid cells have become available enabling us to precisely map the contacts between the EBV episome(s) and the human host genome. Using available Hi-C data at 10kb resolution, we have identified nearly 15000 reproducible contacts between EBV episome and human genome. These contacts are highly enriched in chromatin regions denoted by typical or super enhancers and active marks including histone H3 K27ac, K4me1, K79me2 and K4me2. Additionally, these contacts are highly enriched at loci bound by host transcription factors that regulate B cell growth (e.g. IKZF1 and RUNX3), factors that enhance cell proliferation (e.g. HDGF) or factors that promote viral replication (e.g. NBS1 and NFIC). EBV contacts show nearly two-fold enrichment in host regions bound by EBV EBNA2 and EBNA3B transcription factors. Chromosome conformation capture coupled with sequencing (4C-seq) using the EBV oriP as a “bait” loci in lymphoblastoid cells further confirmed contact with active chromatin regions. Collectively, our analysis supports the interaction between EBV episome(s) and active regions of human genome in lymphoblastoid cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154052 | GEO | 2020/09/23

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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Epstein-Barr Virus episome physically interacts with active regions of the host genome in lymphoblastoid cells

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