天然无序区域在Ash1/Ash1L组蛋白甲基转移酶活化过程中的调控作用

组蛋白甲基化修饰与基因的转录调控密切相关,其中果蝇的Ash1以及哺乳动物的同源蛋白Ash1L是催化组蛋白H3上36位赖氨酸进行单甲基化和双甲基化的甲基转移酶.由于存在一个自抑制环区阻挡了底物的结合位点,Ash1/Ash1L本身的组蛋白甲基转移酶活性是很低的.但与Mrg15结合后,Ash1/Ash1L从原来的自抑制态转变为活化态.最近,Ash1L与Mrg15结合后复合物的晶体结构被成功解析出来,使之可以揭示Ash1L与Mrg15之间的特异相互作用以及Mrg15激活Ash1L的机理.我们通过比较Ash1L/Mrg15复合物的两个晶体结构来讨论Ash1L分子中的天然无序区域在其活化过程中所起的重要调控作用.     

甲基转移酶对鼻咽癌细胞中DLC-1基因表达的影响

肝癌缺失基因-1(deleted in liver cancer-1,DLC-1)在多种肿瘤中呈现表达缺失或表达下调,这种异常表达主要与由DNA甲基转移酶(DNA methyltransferases,DNMTs)参与的启动子区异常甲基化有关。RT-PCR结果显示DLC-1在永生化鼻咽上皮细胞NP69和干扰DNMTs的5-8F细胞中的表达水平较未干扰的鼻咽癌细胞明显升高。甲基化特异性PCR(methylation-specific PCR,MSPCR)结果则表明DLC-1启动子区在表达下调或缺失的鼻咽癌细胞中均存在异常高甲基化,而干扰DNMTs后5-8F细胞中DLC-1启动子区甲基化状态被逆转,其中特异性干扰DNMT1后效果略为显著,提示DNA甲基转移酶活性对于鼻咽癌中DLC-1启动子区甲基化水平具有重要的调控作用,而DNMT1的调控作用更为突出。     

Epigenetic Silencing of CHOP Expression by the Histone Methyltransferase EHMT1 Regulates Apoptosis in Colorectal Cancer Cells

Colorectal cancer (CRC) has a high mortality rate among cancers worldwide. To reduce this mortality rate, chemotherapy (5-fluorouracil, oxaliplatin, and irinotecan) or targeted therapy (bevacizumab, cetuximab, and panitumumab) has been used to treat CRC. However, due to various side effects and poor responses to CRC treatment, novel therapeutic targets for drug development are needed. In this study, we identified the overexpression of EHMT1 in CRC using RNA sequencing (RNA-seq) data derived from TCGA, and we observed that knocking down EHMT1 expression suppressed cell growth by inducing cell apoptosis in CRC cell lines. In Gene Ontology (GO) term analysis using RNA-seq data, apoptosis-related terms were enriched after EHMT1 knockdown. Moreover, we identified the CHOP gene as a direct target of EHMT1 using a ChIP (chromatin immunoprecipitation) assay with an anti-histone 3 lysine 9 dimethylation (H3K9me2) antibody. Finally, after cotransfection with siEHMT1 and siCHOP, we again confirmed that CHOP-mediated cell apoptosis was induced by EHMT1 knockdown. Our findings reveal that EHMT1 plays a key role in regulating CRC cell apoptosis, suggesting that EHMT1 may be a therapeutic target for the development of cancer inhibitors.     

组蛋白甲基转移酶MLL1的结构与功能研究进展

组蛋白甲基转移酶MLL1因其基因易位重排所引起的混合系白血病（mixed lineage leukemia）而得名。MLL1蛋白在基因调控、细胞增殖、生长分化等正常生理功能中发挥着重要作用,染色体易位重排所产生的MLL1融合蛋白则与急性白血病的发生发展密切相关。目前人们对MLL1蛋白的结构和功能研究取得了很大的进展,为以MLL1和其相互作用蛋白为靶点的新型MLL白血病药物设计奠定了坚实的基础。     

Testis-Specific Expression of a Novel Human H3 Histone Gene

We have investigated the expression of a recently described, solitary human H3 histone gene. Using RNase protection assays, the corresponding mRNA could only be detected in RNA preparations from human testis, whereas several human cell lines and somatic tissues did not exhibit expression of this gene.In situhybridization of sections from human testis revealed expression to be confined to primary spermatocytes. In addition to H1t, this novel H3 gene, which is located on chromosome 1, is the second tissue-specific human histone gene that has been found to be expressed solely in the testis.     

p53-p21通路抑制组蛋白甲基转移酶NSD2的表达

NSD2(nuclear receptor-binding SET domain 2)是一种在黑色素瘤等多种肿瘤细胞中高表达的组蛋白甲基转移酶,其在Wolf-Hirschhorn综合症(wolf-Hirschhorn syndrome,WHS)和多发性骨髓瘤(multiple myeloma,MM)疾病中表达异常的原因已经得到了较好的阐明。而NSD2在其它肿瘤中的表达为何失调还未阐明。本研究选用p53野生型的恶性黑色素瘤细胞系92-1作为细胞模型,采用DNA损伤试剂依托泊苷处理和RNA干扰技术,通过定量PCR和蛋白质免疫印迹的方法首次证实了p53-p21通路对NSD2具有抑制作用。     

Histone H3K79 methylation by DOT1L promotes Aurora B localization at centromeres in mitosis

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