London Regional Cancer Program, Children's Health Research Institute, London, ON, Canada.
London Health Sciences Research Institute, London, ON, Canada.
EMBO J. 2023 Dec 11;42(24):e114462. doi: 10.15252/embj.2023114462. Epub 2023 Nov 7.
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.
哺乳动物细胞通过形成异染色质来抑制重复基因组序列的表达。然而，异位重复表达的后果仍不清楚。在这里，我们证明了 Polycomb 抑制复合物 2（PRC2）的催化亚基 EZH2 的抑制剂会刺激静止脾 B 细胞中重复序列的错误表达和细胞死亡。B 细胞对这些药物特别敏感，因为它们表现出高水平的组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）和相应的重复元件处低 DNA 甲基化。我们生成了一种模式识别受体功能丧失的小鼠模型，称为 RIC，其在 Rigi（编码 RIG-I）、Ifih1（MDA5）和 Cgas 中具有突变。在野生型和 RIC 突变 B 细胞中，EZH2 抑制导致重复元件处的 H3K27me3 丢失，并上调其表达。然而，NF-κB 依赖性炎症趋化因子的表达和随后的细胞死亡被 RIC 突变所抑制。我们进一步表明，癌细胞中 EZH2 的抑制需要相同的模式识别受体来激活干扰素反应。总之，这些结果揭示了 EZH2 抑制剂在 B 细胞中诱导的趋化因子表达是对基因组重复表达的一种新的炎症反应。鉴于 EZH2 抑制剂和 Epstein-Barr 病毒感染诱导的基因重叠，这种反应可以被描述为一种病毒模拟。
