组蛋白去甲基化酶UTX与胚胎发育及疾病关系

组蛋白3赖氨酸27(histone 3 lysine 27, H3K27)去甲基化酶UTX(ubiquitously transcribed tetratricopeptide repeat on chromosome X, UTX)为X染色体上重复的转录三十四肽,是组蛋白3赖氨酸4(histone 3 lysine 4, H3K4)甲基转移酶复合物MLL2(mixed-lineage leukemia 2, MLL2)中的一员,可调节同源基因HOX(homeobox, HOX)和视网膜母细胞瘤基因RB(retinoblastoma, RB)转录谱系. UTX与BRG1-SWI/SNF重塑复合物(Brg1-containing ATPase-dependent Swi/Snf chromatin-remodeling complex, BRG1-SWI/SNF)相互作用促进染色质重塑. 因其在细胞的正确再编程、胚胎发育和组织特异性分化中扮演重要角色,UTX失活或缺失会导致癌症、胚胎发育缺陷等疾病的发生. 本文将对近年来UTX在胚胎发育及与疾病关系方面的研究进展做一综述.     

PI3K/AKT信号通路调控Myogenin和MCK基因的表达

骨骼肌分化过程受多个信号通路调控, PI3K/AKT信号通路是其中最重要的信号转导通路之一。PI3K/AKT信号通路可以调控骨骼肌分化, 但在染色质水平上的调控机制还不是很清楚。文章以小鼠成肌细胞(C2C12)为研究材料, 采用免疫印迹、染色质免疫共沉淀(Chromatin immunoprecipitation, ChIP)、定量PCR (Q-PCR)的方法研究PI3K/AKT信号通路调控Myogenin和MCK基因的表达。研究发现, C2C12细胞分化过程中添加PI3K/AKT信号通路激活剂处理24 h, Myogenin和MCK蛋白表达水平显著升高, 组蛋白H3K27me3去甲基化酶UTX的表达也升高, H3K27me3在Myogenin基因启动子区和MCK基因启动子及增强子区的富集与对照组相比显著降低。用PI3K/AKT信号通路抑制剂处理, 结果相反。因此, PI3K/AKT信号通路可能通过调控组蛋白去甲基化酶UTX的表达活性改变靶基因的H3K27me3的富集进而调控骨骼肌分化。     

The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner

Aging is accompanied by alterations in epigenetic marks that control chromatin states, including histone acetylation and methylation. Enzymes that reversibly affect histone marks associated with active chromatin have recently been found to regulate aging in Caenorhabditis elegans. However, relatively little is known about the importance for aging of histone marks associated with repressed chromatin. Here, we use a targeted RNAi screen in C. elegans to identify four histone demethylases that significantly regulate worm lifespan, UTX‐1, RBR‐2, LSD‐1, and T26A5.5. Interestingly, UTX‐1 belongs to a conserved family of histone demethylases specific for lysine 27 of histone H3 (H3K27me3), a mark associated with repressed chromatin. Both utx‐1 knockdown and heterozygous mutation of utx‐1 extend lifespan and increase the global levels of the H3K27me3 mark in worms. The H3K27me3 mark significantly drops in somatic cells during the normal aging process. UTX‐1 regulates lifespan independently of the presence of the germline, but in a manner that depends on the insulin‐FoxO signaling pathway. These findings identify the H3K27me3 histone demethylase UTX‐1 as a novel regulator of worm lifespan in somatic cells.     

组蛋白去甲基酶UTX在发育和疾病中的作用

UTX(ubiquitously transcribed tetratricopeptide repeat,X chromosome)是抑制性组蛋白H3K27me3的特异性去甲基化酶,和甲基转移酶PRC2共同调控H3K27me3。此外,UTX也是组蛋白H3K4甲基转移酶MLL3/MLL4的组成部分。UTX参与胚胎发育、HOX基因的表达和重编程等生命过程。在歌舞伎综合征中,UTX突变是关键的致病因素。同时,UTX作为肿瘤抑制因子参与多种实体肿瘤和血液肿瘤的产生。该文总结了UTX在正常发育和疾病发生中的作用及近期研究的重大突破,并结合我们的研究探讨了UTX对体细胞重编程的影响。     

Epigenomic Landscape of Human Fetal Brain,Heart, and Liver

The epigenetic regulation of spatiotemporal gene expression is crucial for human development. Here, we present whole-genome chromatin immunoprecipitation followed by high throughput DNA sequencing (ChIP-seq) analyses of a wide variety of histone markers in the brain, heart, and liver of early human embryos shortly after their formation. We identified 40,181 active enhancers, with a large portion showing tissue-specific and developmental stage-specific patterns, pointing to their roles in controlling the ordered spatiotemporal expression of the developmental genes in early human embryos. Moreover, using sequential ChIP-seq, we showed that all three organs have hundreds to thousands of bivalent domains that are marked by both H3K4me3 and H3K27me3, probably to keep the progenitor cells in these organs ready for immediate differentiation into diverse cell types during subsequent developmental processes. Our work illustrates the potentially critical roles of tissue-specific and developmental stage-specific epigenomes in regulating the spatiotemporal expression of developmental genes during early human embryonic development.     

MER-ERK信号通路调控H3K27me3甲基化酶和去甲基化酶基因表达的研究

在人的某些癌症细胞中,组蛋白H3K27me3甲基化酶EZH2基因存在过表达的现象,很多研究已经证明,这可能是受MEK ERK信号通路调控的.为了确定这种调控模式在小鼠细胞系中是否同样存在,以及MEK ERK信号通路是否同时调控H3K27me3甲基化酶EZH1基因和去甲基化酶UTX、JMJD3基因的表达,用RT PCR和Western印迹方法检测不同浓度的MEK ERK抑制剂U0126（0、10、20、40 μmol/L）对C2C12、C127、NIH3T3三种小鼠细胞系处理后,EZH1、EZH2基因和UTX、JMJD3基因表达变化.结果显示：MEK-ERK抑制剂处理后,3种细胞中EZH1和EZH2基因的表达与对照相比都有不同程度的降低,其中EZH2基因表达变化在C2C12、NIH3T3两种细胞达到显著水平(P<0.05). H3K27me3去甲基化酶UTX、JMJD3基因在3种细胞中表达均有升高,JMJD3升高达到显著水平（P<0.05).因此,在小鼠细胞系MEK ERK信号通路可能参与调控EZH2、JMJD3基因的表达,但对EZH1、UTX基因的表达调控作用不明显.
关键词MEK ERK信号通路;     

The C. elegans H3K27 demethylase UTX-1 is essential for normal development, independent of its enzymatic activity

Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3. We demonstrate that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Consistent with its homology to UTX, UTX-1 regulates global levels of H3K27me2/3 in C. elegans. Surprisingly, we found that the catalytic activity is not required for the developmental function of this protein. Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL), and genetic analysis indicates that the defects associated with loss of UTX-1 are likely mediated by compromised SET-16/UTX-1 complex activity. Taken together, these results demonstrate that UTX-1 is required for many aspects of nematode development; but, unexpectedly, this function is independent of its enzymatic activity.     

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.