MYC altered Epstein–Barr virus (EBV) chromatin structure to maintain latency in Burkitt lymphoma.
Major Finding: MYC altered Epstein–Barr virus (EBV) chromatin structure to maintain latency in Burkitt lymphoma.
Mechanism: MYC bound specific enhancer boxes, blocking looping to a key lytic-cycle regulator gene's promoter.
Impact: This reveals a mechanism of EBV latency, which may uncover vulnerabilities in Burkitt lymphoma.
Epstein–Barr virus (EBV) infection is linked to several cancers. In EBV-associated B-cell malignancies such as Burkitt lymphoma, EBV latency is commonly observed, and it has been suggested that reversing latency and promoting lytic infection may make tumor cells susceptible to antiviral drugs such as ganciclovir. Guo, Jiang, and colleagues performed a CRISPR–Cas9-based knockout screen in EBV+ Burkitt lymphoma cells to identify key mediators of EBV latency. This pinpointed epigenetic regulators that were grouped into an interaction network that was centered on the proto-oncoprotein and transcription factor MYC. Experiments in two Burkitt lymphoma cell lines, one infected with the type II EBV strain and the other with the more common type I EBV strain, revealed that MYC was required for maintenance of EBV latency. Mechanistically, MYC appeared to suppress expression of the EBV gene BZLF1, which encodes a master regulator of the B-cell lytic cycle, via interactions with the BZLF1 promoter. Investigating other screen hits tied to MYC revealed that the cohesin subunit SMC1A, members of the transcriptional coactivator complexes STAGA and Mediator, and the facilitated chromatin transcription (FACT) complex supported MYC expression to maintain EBV latency in Burkitt lymphoma cells. Notably, in a mouse xenograft model of EBV+ Burkitt lymphoma, treatment with a FACT inhibitor increased expression of EBV lytic genes and BZLF1 protein in tumors in a dose-dependent fashion. Further experiments implied that MYC binding to enhancer boxes of EBV origins of lytic replication (oriLyt) binding may be required for maintenance of EBV latency and demonstrated that MYC binding to these sites induced high-order alterations in EBV genome architecture. Specifically, experimental evidence suggested that, in the absence of MYC, oriLyt and terminal-repeat regions looped to the BZLF1 promoter to enable initiation of the lytic cycle. Collectively, these results provide a molecular model explaining how the EBV lytic cycle can be activated in Burkitt lymphoma cells, providing insights that may be useful in the development of drugs to reverse disease-promoting latency.
Guo R, Jiang C, Zhang Y, Govande A, Trudeau SJ, Chen F, et al. MYC controls the Epstein-Barr virus lytic switch. Molec Cell 2020 Apr 20 [Epub ahead of print].
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