EZH2 inhibition stimulates repetitive element expression and viral mimicry in resting splenic B cells.

Mammalian cells repress expression of repetitive genomic sequences by forming heterochromatin. However, the consequences of ectopic repeat expression remain unclear. Here we demonstrate that inhibitors of EZH2, the catalytic subunit of the Polycomb repressive complex 2 (PRC2), stimulate repeat misexpression and cell death in resting splenic B cells. B cells are uniquely sensitive to these agents because they exhibit high levels of histone H3 lysine 27 trimethylation (H3K27me3) and correspondingly low DNA methylation at repeat elements. We generated a pattern recognition receptor loss‐of‐function mouse model, called RIC, with mutations in Rigi (encoding for RIG‐I), Ifih1 (MDA5), and Cgas. In both wildtype and RIC mutant B cells, EZH2 inhibition caused loss of H3K27me3 at repetitive elements and upregulated their expression. However, NF‐κB‐dependent expression of inflammatory chemokines and subsequent cell death was suppressed by the RIC mutations. We further show that inhibition of EZH2 in cancer cells requires the same pattern recognition receptors to activate an interferon response. Together, the results reveal chemokine expression induced by EZH2 inhibitors in B cells as a novel inflammatory response to genomic repeat expression. Given the overlap of genes induced by EZH2 inhibitors and Epstein–Barr virus infection, this response can be described as a form of viral mimicry. Synopsis: Expression of repetitive genomic elements can activate inflammatory signaling via binding of pattern recognition receptors. Here, inhibition of PRC2 subunit EZH2 is shown to cause repeat element expression and activation of different cytokine or chemokine pathways in normal and transformed cells. EZH2 inhibition induces sterile inflammation and cell death selectively in resting splenic B cells.Cytosolic pattern recognition receptors are required to activate inflammation induced by EZH2 inhibition.Resting B cells respond to EZH2 inhibition by inducing NF‐kB pathway‐dependent chemokine expression, while cancer cells activate an interferon expression program. [ABSTRACT FROM AUTHOR]