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Nuclear Lamina binds the EBV genome during latency and regulates viral gene expression

By Lisa Beatrice Caruso, Rui Guo, Sarah Boyle, Kelsey Keith, Jozef Madzo, Jason Wasserman, Andrew Kossenkov, Benjamin Gewurz, Italo Tempera

Posted 05 Aug 2021
bioRxiv DOI: 10.1101/2021.08.05.455214

The Epstein Barr virus (EBV) establishes a persistent latent infection in almost 90% of the population worldwide. EBV latent infection is associated with several malignancies of epithelial and lymphoid origin. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes. Latent genes are expressed in different patterns that are referred to as latency types. Latency types coincide with varying stages of EBV infection and various malignancies. Our previous work demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including nuclear lamina, regulate chromatin composition and chromatin architecture. The interaction with nuclear lamina has already been studied in the context of EBV lytic reactivation. Still, the role of nuclear lamina in controlling EBV latency has not been investigated. Here, we reported that nuclear lamina is also another essential epigenetic regulator of the EBV episome. First, we observed that in B cells, EBV infection affects the composition of nuclear lamina by inducing the expression of Lamin A/C, and Lamin A/C is present only in EBV+ B cells expressing the Type III latency program. By ChIP-seq, we determined that lamins, Lamin B1 and Lamin A/C, bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-seq, we observed that the knock-out of Lamin A/C alters EBV gene expression in B cells and decreases H3K9me2 levels across the viral genome. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral genes expression during latency, suggesting a restrictive function of the nuclear lamina in the host response against the intrusion of viral DNA into the nucleus.

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