The localization of histone H3K27me3 demethylase Jmjd3 is dynamically regulated

Jmjd3 is required for cellular differentiation and senescence, and inhibits the induction of pluripotent stem cells by demethylating histone 3 lysine 27 trimethylation (H3K27me3). Although recent studies reveal crucial biological roles for Jmjd3, it is unclear how its demethylase activity is controlled. Here, we show that nuclear localization of Jmjd3 is required for effective demethylation of H3K27me3. Our subcellular localization analysis of Jmjd3 shows that the N-terminal region of the protein is responsible for its nuclear placement, whereas the C-terminal region harboring the catalytic Jumonji C (JmjC) domain cannot situate into the nucleus. We identify two classical nuclear localization signals (cNLSs) in the N-terminal domain of Jmjd3. Forced nuclear emplacement of the catalytic domain of Jmjd3 by fusion with a heterologous cNLS significantly enhances its H3K27me3 demethylation activity. A dynamic nucleocytoplasmic shuttling of endogenous Jmjd3 occurs in mouse embryonic fibroblasts. Jmjd3 is localized both into the cytoplasm and the nucleus, and its nuclear export is dependent on Exportin-1, as treatment with leptomycin B triggers nuclear accumulation of Jmjd3. These results suggest that the subcellular localization of Jmjd3 is dynamically regulated and has pivotal roles for H3K27me3 status.     

The localization of histone H3K27me3 demethylase Jmjd3 is dynamically regulated

Jmjd3 is required for cellular differentiation and senescence, and inhibits the induction of pluripotent stem cells by demethylating histone 3 lysine 27 trimethylation (H3K27me3). Although recent studies reveal crucial biological roles for Jmjd3, it is unclear how its demethylase activity is controlled. Here, we show that nuclear localization of Jmjd3 is required for effective demethylation of H3K27me3. Our subcellular localization analysis of Jmjd3 shows that the N-terminal region of the protein is responsible for its nuclear placement, whereas the C-terminal region harboring the catalytic Jumonji C (JmjC) domain cannot situate into the nucleus. We identify two classical nuclear localization signals (cNLSs) in the N-terminal domain of Jmjd3. Forced nuclear emplacement of the catalytic domain of Jmjd3 by fusion with a heterologous cNLS significantly enhances its H3K27me3 demethylation activity. A dynamic nucleocytoplasmic shuttling of endogenous Jmjd3 occurs in mouse embryonic fibroblasts. Jmjd3 is localized both into the cytoplasm and the nucleus, and its nuclear export is dependent on Exportin-1, as treatment with leptomycin B triggers nuclear accumulation of Jmjd3. These results suggest that the subcellular localization of Jmjd3 is dynamically regulated and has pivotal roles for H3K27me3 status.     

组蛋白H3K27去甲基化酶与肿瘤发生

组蛋白甲基化是一种重要的表观遗传学修饰,在基因表达调节方面发挥着重要的作用.组蛋白H3赖氨酸27三甲基化（H3K27me3）是一种抑制性组蛋白标记,可被去甲基化酶UTX和JMJD3催化而移去甲基.UTX和JMJD3通过激活HOX基因而参与细胞分化和多能细胞抑制过程.在多种肿瘤中检测到UTX和JMJD3突变或表达下降,同时多种基因启动子区H3K27me3含量增多.UTX和JMJD3均被看作肿瘤抑制基因,其中UTX调节了RB依赖的细胞命运控制,而JMJD3通过激活INK4b-ARF-INK4a位点而参与了癌基因诱导的衰老.组蛋白H3K27去甲基化酶与肿瘤发生的研究使我们对癌症发展过程有了更好的理解,同时也为癌症诊断和治疗提供了新靶点.