The three-dimensional structure of Epstein-Barr virus genome varies by latency type and is regulated by PARP1 enzymatic activity

Sarah M. Morgan, Hideki Tanizawa, Lisa Beatrice Caruso, Michael Hulse, Andrew Kossenkov, Jozef Madzo, Kelsey Keith, Yinfei Tan, Sarah Boyle, Paul M. Lieberman and Italo Tempera ()
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Sarah M. Morgan: The Wistar Institute
Hideki Tanizawa: University of Oregon
Lisa Beatrice Caruso: The Wistar Institute
Michael Hulse: Lewis Katz School of Medicine at Temple University
Andrew Kossenkov: The Wistar Institute
Jozef Madzo: The Coriell Institute for Medical Research
Kelsey Keith: The Coriell Institute for Medical Research
Yinfei Tan: Fox Chase Cancer Center
Sarah Boyle: The Wistar Institute
Paul M. Lieberman: The Wistar Institute
Italo Tempera: The Wistar Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Epstein-Barr virus (EBV) persists in human B-cells by maintaining its chromatinized episomes within the nucleus. We have previously shown that cellular factor Poly [ADP-ribose] polymerase 1 (PARP1) binds the EBV genome, stabilizes CTCF binding at specific loci, and that PARP1 enzymatic activity correlates with maintaining a transcriptionally active latency program. To better understand PARP1’s role in regulating EBV latency, here we functionally characterize the effect of PARP enzymatic inhibition on episomal structure through in situ HiC mapping, generating a complete 3D structure of the EBV genome. We also map intragenomic contact changes after PARP inhibition to global binding of chromatin looping factors CTCF and cohesin across the EBV genome. We find that PARP inhibition leads to fewer total unique intragenomic interactions within the EBV episome, yet new chromatin loops distinct from the untreated episome are also formed. This study also illustrates that PARP inhibition alters gene expression at the regions where chromatin looping is most effected. We observe that PARP1 inhibition does not alter cohesin binding sites but does increase its frequency of binding at those sites. Taken together, these findings demonstrate that PARP has an essential role in regulating global EBV chromatin structure and latent gene expression.

Date: 2022
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DOI: 10.1038/s41467-021-27894-1

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