Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

中文翻译：

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PRMT5 介导的组蛋白精氨酸甲基化拮抗多梳复合物 PRC2 的转录抑制。


蛋白精氨酸甲基转移酶 5 (PRMT5) 催化组蛋白 H3 和 H4 中精氨酸残基的对称二甲基化，这些标记通常与转录抑制相关。然而，我们发现PRMT5抑制或缺失导致更多基因被下调而不是上调，这表明PRMT5也可以充当转录激活剂。事实上，PRMT5 缺陷细胞中组蛋白 H3K27me3 的整体水平有所增加。尽管 PRMT5 不直接影响 PRC2 酶活性，但 PRMT5 对组蛋白 H3 的甲基化消除了 PRC2 随后对其的甲基化。用 EZH2 抑制剂处理 AML 细胞部分恢复了约 50% 最初因 PRMT5 抑制而下调的基因的表达，表明增加的 H3K27me3 可能直接或间接有助于这些基因的转录抑制。事实上，ChIP 测序分析证实，在 PRMT5 抑制的细胞中，四分之一的这些基因的启动子区域的 H3K27me3 水平有所增加。有趣的是，在几种白血病细胞系中使用 EZH2 抑制剂治疗也可以部分恢复 PRMT5 抑制的抗增殖作用。因此，PRMT5 介导的组蛋白标记之间的串扰有助于其功能效应。