组蛋白甲基转移酶的研究进展

组蛋白的甲基化修饰主要是由一类含有SET结构域的蛋白来执行的, 组蛋白甲基化修饰参与异染色质形成、基因印记、X染色体失活和转录调控等多种主要生理功能, 组蛋白的修饰作用是表观遗传学研究的一个重要领域。组蛋白甲基化的异常与肿瘤发生等多种人类疾病相关, 可以特异性地激活或者抑制基因的转录活性。研究发现, 组蛋白甲基转移酶的作用对象不仅仅限于组蛋白, 某些非组蛋白也可以被组蛋白甲基转移酶甲基化, 这将为探明细胞内部基因转录、信号转导、甚至个体的发育和分化机制提供更广阔的空间。     

真菌组蛋白赖氨酸甲基转移酶的研究进展

甲基化修饰是蛋白翻译后修饰的主要方式之一。真菌中,多种赖氨酸甲基转移酶能够执行组蛋白特定位点上赖氨酸的甲基化。组蛋白上赖氨酸的甲基化与真菌DNA的复制、转录以及异染色质的形成相关。甲基化参与了多种生物学过程,如真菌发育、昼夜节律调节、次级代谢基因簇表达、水解酶合成、致病真菌毒力形成。本文结合笔者工作,对目前真菌中已经发现的组蛋白赖氨酸甲基转移酶的命名、分类、结构域特征、催化域的三维结构以及它们所执行的甲基化在各种真菌中的作用进行了总结,提出了目前研究的不足并对未来的研究方向和内容进行了展望。     

组蛋白赖氨酸甲基化在表观遗传调控中的作用

组蛋白赖氨酸的甲基化在表观遗传调控中起着关键作用。组蛋白H3的K4、K9、K27、K36、K79和H4的K20均可被甲基化。组蛋白H3第9位赖氨酸的甲基化与基因的失活相关连; 组蛋白H3第4位赖氨酸和第36位赖氨酸的甲基化与基因的激活相关连; 组蛋白H3第27位赖氨酸的甲基化与同源盒基因沉默、X染色体失活、基因印记等基因沉默现象有关; 组蛋白H3第79位赖氨酸的甲基化与防止基因失活和DNA修复有关。与此同时, 组蛋白的去甲基化也受到更为广泛的关注。 关键词: 组蛋白赖氨酸甲基转移酶; 组蛋白赖氨酸甲基化; 组蛋白去甲基化     

JMJD3 is a histone H3K27 demethylase

Histone methylation is an important epigenetic phenomenon that participates in a diverse array of cellular processes and has been found to be associated with cancer. Recent identification of several histone demethylases has proved that histone methylation is a reversible process. Through a candidate approach, we have biochemically identified JMJD3 as an H3K27 demethylase. Transfection of JMJD3 into HeLa cells caused a specific reduction oftrimethyl H3K27, but had no effect on di-and monomethyl H3K27, or histone lysine methylations on H3K4 and H3K9. The enzymatic activity requires the JmjC domain and the conserved histidine that has been suggested to be important for a cofactor binding. In vitro biochemical experiments demonstrated that JMJD3 directly catalyzes the demethylation. In addition, we found that JMJD3 is upregulated in prostate cancer, and its expression is higher in metastatic prostate cancer. Thus, we identified JMJD3 as a demethylase capable of removing the trimethyl group from histone H3 lysine 27 and upregulated in prostate cancer.     

Structural basis for product specificities of MLL family methyltransferases

1. Download : Download high-res image (217KB)
2. Download : Download full-size image

     

Glimpses of evolution: heterochromatic histone H3K9 methyltransferases left its marks behind

In eukaryotes, histone methylation is an epigenetic mechanism associated with a variety of functions related to gene regulation or genomic stability. Recently analyzed H3K9 methyltransferases (HMTases) as SUV39H1, Clr4p, DIM-5, Su(var)3-9 or SUVH2 are responsible for the establishment of histone H3 lysine 9 methylation (H3K9me), which is intimately connected with heterochromatinization. In this review, available data will be evaluated concerning (1) the phylogenetic distribution of H3K9me as heterochromatin-specific histone modification and its evolutionary stability in relation to other epigenetic marks, (2) known families of H3K9 methyltransferases, (3) their responsibility for the formation of constitutive heterochromatin and (4) the evolution of Su(var)3-9-like and SUVH-like H3K9 methyltransferases. Compilation and parsimony analysis reveal that histone H3K9 methylation is, next to histone deacetylation, the evolutionary most stable heterochromatic mark, which is established by at least two subfamilies of specialized heterochromatic HMTases in almost all studied eukaryotes.     

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.     

Distinct localization of histone H3 methylation in the vegetative nucleus of lily pollen

We analysed the distribution of histone H3 modifications in the nucleus of the vegetative cell (the vegetative nucleus) during pollen development in lily (Lilium longiflorum). Among the modifications specifically and/or abundantly present in the vegetative nucleus, dimethylation of histone H3 at lysine 9 (H3K9me2) and lysine 27 (H3K27me2) were found in heterochromatin, whereas trimethylation of histone H3 at lysine 27 (H3K27me3) was localized in euchromatin in the vegetative nucleus. Such unique localization of the histone H3 methylation marks, particularly of H3K27me3, within a nucleus was not observed in lily nuclei other than the vegetative nucleus. The level of H3K27me3 increased in the euchromatic region of the vegetative nucleus during pollen maturation. The results suggest that H3K27me3 controls the gene expression of the vegetative cell during pollen maturation.     

Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

1. Download : Download high-res image (171KB)
2. Download : Download full-size image