Research squareJan 29, 2025

A Protein Complex That Strongly Limits Reactivation of Epstein-Barr Virus

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 16, 2026

Abstract

Epstein-Barr virus (EBV) is associated with approximately 1.5% of human cancers.

EBV may remain latent in human cells due to nearly 80 viral genes being silenced by epigenetic mechanisms.
Key host factors identified for maintaining EBV latency include the histone demethylase LSD1 and its co-repressors ZNF217 and CoREST.
Knocking out LSD1, ZNF217, or CoREST can trigger EBV reactivation.
LSD1 inhibitors may enhance the effectiveness of antiviral treatments like ganciclovir in EBV-associated cancers.
LSD1 and ZNF217 are found to co-bind to the BZLF1 promoter, which activates the EBV lytic cycle.
Increased levels of activating marks on histone 3 lysine 4 at the BZLF1 promoter are associated with LSD1 depletion.

Simplified

Epstein-Barr virus (EBV) contributes to ~1.5% of human cancers, including lymphomas, gastric and nasopharyngeal carcinomas. In most of these, nearly 80 viral lytic genes are silenced by incompletely understood epigenetic mechanisms, precluding use of antiviral agents such as ganciclovir to treat the 200,000 EBV-associated cancers/year. To identify host factors critical for EBV latency, we performed a human genome-wide CRISPR-Cas9 screen in Burkitt B-cells. Top hits included the lysine-specific histone demethylase LSD1 and its co-repressors ZNF217 and CoREST. LSD1 removes histone 3 lysine 4 (H3K4) and histone 3 lysine 9 (H3K9) methylation marks to downmodulate chromatin activation. LSD1, ZNF217 or CoREST knockout triggered EBV reactivation, as did a LSD1 small molecule antagonist, whose effects were additive with histone deacetylase inhibition. LSD1 blockade reactivated EBV in Burkitt lymphoma, gastric carcinoma and nasopharyngeal carcinoma models, sensitized cells to ganciclovir cytotoxicity and induced EBV reactivation in murine xenografts. ZNF217 and LSD1 co-occupied the EBV immediate early gene BZLF1 promoter, which drives B-cell lytic cycle, as well as to theenhancer regions recently implicated in EBV reactivation. LSD1 depletion increased levels of activating histone 3 lysine 4 (H3K4) methylation but not repressive histone lysine 9 methylation marks at BZLF1 andand induced their interaction by long-range DNA looping. An orthogonal CRISPR screen highlighted a key H3K4 methyltransferase KMT2D role in driving EBV reactivation. Our results highlight H3K4 methylation as a major EBV lytic switch regulator and suggest novel therapeutic approaches. oriLyt oriLyt

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A Protein Complex That Strongly Limits Reactivation of Epstein-Barr Virus

Abstract

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