Center for Circadian Clocks, Soochow University, Suzhou, Jiangsu, PR China.
School of Biology & Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu, PR China.
Nucleic Acids Res. 2018 Apr 20;46(7):3382-3399. doi: 10.1093/nar/gky101.
EZH2 is a subunit of polycomb repressive complex 2 (PRC2) that silences gene transcription via H3K27me3 and was shown to be essential for mammalian liver circadian regulation and hematopoiesis through gene silencing. Much less, however, is known about how Ezh2 acts in live zebrafish. Here, we show that zebrafish ezh2 is regulated directly by the circadian clock via both E-box and RORE motif, while core circadian clock genes per1a, per1b, cry1aa and cry1ab are down-regulated in ezh2 null mutant and ezh2 morphant zebrafish, and either knockdown or overexpression of ezh2 alters locomotor rhythms, indicating that Ezh2 is required for zebrafish circadian regulation. In contrast to its canonical silencing function, zebrafish Ezh2 up-regulates these key circadian clock genes independent of histone methyltransferase activity by directly binding to key circadian clock proteins. Similarly, Ezh2 contributes to hematopoiesis by enhancing expression of hematopoietic genes such as cmyb and lck. Together, our findings demonstrate for the first time that Ezh2 acts in both circadian regulation and hematopoiesis independent of silencing PRC2.
EZH2 是多梳抑制复合物 2 (PRC2) 的一个亚基，通过 H3K27me3 沉默基因转录，并且通过基因沉默被证明对哺乳动物肝脏昼夜节律调节和造血至关重要。然而，关于 Ezh2 在活体斑马鱼中的作用却知之甚少。在这里，我们表明斑马鱼 ezh2 通过 E 盒和 RORE 基序直接受生物钟调节，而核心生物钟基因 per1a、per1b、cry1aa 和 cry1ab 在 ezh2 缺失突变体和 ezh2 嵌合体斑马鱼中下调，并且 ezh2 的敲低或过表达都会改变运动节律，表明 Ezh2 是斑马鱼昼夜节律调节所必需的。与它的典型沉默功能相反，斑马鱼 Ezh2 通过直接结合关键生物钟蛋白，独立于组蛋白甲基转移酶活性，上调这些关键生物钟基因。同样，Ezh2 通过增强造血基因如 cmyb 和 lck 的表达来促进造血。总之，我们的研究结果首次表明，Ezh2 独立于沉默 PRC2 参与昼夜节律调节和造血。
