肿瘤发生的表观遗传机制和表观治疗方法

表观遗传包括通过DNA甲基化、组蛋白修饰、染色质重塑和RNA干扰等,通过这些机制干扰了正常基因的功能。越来越多的研究表明,DNA甲基化和组蛋白修饰异常,在多种肿瘤的发生中起重要作用。本文对表观遗传的分子机制,和同肿瘤发生的关系,以及肿瘤的表观治疗策略作了详细的综述。     

人消化道肿瘤的表观遗传学研究

肿瘤的发生机制中有遗传学说和表观遗传学说．后者研究的主要内容包括DNA甲基化修饰和组蛋白的各种修饰．消化道肿瘤的发生发展存在表观遗传修饰的异常,如癌基因的低甲基化和抑癌基因的高甲基化,也同时存在着组蛋白乙酰化等修饰的紊乱．通过干预表观遗传修饰防治消化道肿瘤具有广阔的应用前景．     

组蛋白甲基化的阅读器识别机制研究进展

 组蛋白甲基化修饰对遗传信息解读有着重要影响,是表观遗传调控的主要机制之一。组蛋白甲基化可以被一类称作"阅读器"的结构域所特异识别并介导下游生物学事件。本文综述了目前已知的组蛋白甲基化阅读器(包括"皇室家族"成员、PHD锌指及BAH 等结构域)的结构特征及其对于甲基化修饰位点和程度特异性识别的分子基础。另外,探讨了表观遗传修饰调控中的组合识别、修饰对话等概念与机制。     

父代肥胖对精子表观遗传跨代继承的影响

父代肥胖会导致精子表观遗传修饰的改变,这种异常的表观遗传修饰会传递至后代,对后代健康产生严重影响.本文主要综述了由于父代肥胖所致的DNA甲基化、组蛋白修饰和非编码RNA等表观遗传修饰的异常及其跨代继承的机制,从表观遗传水平阐述父代肥胖对自身和后代健康的影响,可为后代相关疾病的预防和诊断提供参考资料.     

组蛋白修饰与ES细胞的多能性

胚胎干细胞（ESCs）来源于早期胚胎内细胞群，具有分化和发育多能性和无限增殖与更新能力。组蛋白修饰对ES细胞的自我更新和无限增殖能力及多能性保持具有重要作用。组蛋白修饰是表观遗传调控的关键因素，细胞通过表观遗传状态改变控制基因的选择性表达，实现对细胞分化的调控。并且可以建立调控网络调节ES细胞多能性维持。     

组蛋白甲基化修饰在小鼠早期胚胎发育中的建立与调控

 组蛋白修饰作为重要的表观遗传修饰，在调控胚胎基因表达、胚胎细胞的命运决定及胚胎基因组的稳定性等方面均起了很重要的作用。微量测序技术的发展使从全基因组水平上检测植入前胚胎的组蛋白修饰成为可能。综述了近年来利用该技术对小鼠早期胚胎发育过程中的组蛋白甲基化修饰研究的最新进展，总结了在胚胎基因激活及第一次细胞分化过程中组蛋白H3K4me3和H3K27me3修饰不同的建立和动态变化趋势，这些研究为探索胚胎发育和细胞分化的表观调控机制奠定了基础。     

水稻表观遗传的研究进展

从DNA甲基化、组蛋白修饰的形成条件及其作用机制等方面,对表观遗传学的一些常见的发生机制进行了简要综述,并对表观遗传在水稻中研究的前景作了展望．     

组蛋白去甲基化酶JHDM1的晶体结构研究

组蛋白甲基化是表观遗传修饰方式中的一种,参与异染色质形成、基因印记、X染色体失活和基因转录调控。组蛋白甲基化过程的异常参与多种肿瘤的发生。既往认为组蛋白甲基化是稳定的表观遗传标记,然而最近许多组蛋白特异性去甲基化酶的发现对这一观点提出了挑战。JHDM1是第一个被发现含有JmjC结构域的组蛋白去甲基化酶,它能够特异性地除去H3赖氨酸36位二甲基化和一甲基化修饰,但是不能去除H3赖氨酸36位三甲基化修饰。为了从分子水平上揭示JHDM1的去甲基化催化机理,我们解析了hJHDM1A及其与α-酮戊二酸复合的晶体结构。结构比较揭示α-酮戊二酸的结合能够稳定围绕活性中心的柔性环,这一构像变化对于hJHDM1A发挥去甲基化活性是非常重要的。结合突变试验结果,我们提出了底物的潜在结合位点,结构分析也揭示高度保守的S145对于区分不同的赖氨酸甲基化程度起重要作用。     

表观遗传学研究进展

 概述了表观遗传调节模式、表观遗传调节的效应、植物表观遗传学的研究进展等。在每种细胞中,都会发生一部分特异基因激活、另一部分基因抑制的现象,形成多种基因表达模式。表观遗传指DNA序列不发生变化,而基因表达发生可遗传改变的现象。表观遗传学改变包括DNA甲基化、组蛋白修饰、非编码RNA作用等,产生基因组印记、母性影响、基因沉默、核仁显性、休眠转座子激活等效应。表观遗传变异是环境因素和细胞内遗传物质间交互作用的结果,其效应通过调节基因表达,控制生物学表型来实现。正是因为表观修饰对于维持生物体内环境和各器官系统功能的重要性,表观遗传的异常会引发疾病,这也成为药物和治疗方案设计的着眼点。     

“表观遗传调控的分子机制”研究组——王占新研究组介绍

正表观遗传是指在不改变基因的核苷酸序列的情况下,基因表达性状的可遗传性。表观遗传信息往往通过DNA甲基化、组蛋白修饰和非编码RNA等信息进行传递,对基因的表达调控起重要作用,与机体发育和人类健康密切相关。表观遗传信息由特定的蛋白酶加载,并被特定的结合蛋白识别发挥后续效应,或者被相应的酶去除。表观遗传信息的读写异常与人类的多种疾病相关,因此,研究相关蛋白质复合物的分子机制将为揭示表观遗传调控的奥秘,以及靶向这些蛋白异常导致的人类疾病提供重要分子基础。王占新研究组主要致力于表观遗传信息的修饰以及读取过程中参与的蛋白质复合物分子机制的研究。在高等动物中,表观遗传信息往往是加载在核小体上的,     

组蛋白修饰组合模式研究进展

核小体是染色质的基本结构单位,核小体组蛋白N末端尾部可以发生甲基化、乙酰化等多种共价修饰.组蛋白密码假设多种组蛋白修饰以组合方式发挥作用.自组蛋白密码假设被提出后,组蛋白修饰组合模式成为表观遗传学领域的重要研究内容.在染色质免疫沉淀基因芯片和免疫沉淀高通量测序等相关实验数据的基础上,多种算法被用于研究组蛋白修饰的组合.文章介绍了组蛋白修饰的发生、位点、相关修饰酶以及生物学功能,对组蛋白修饰组合以及与基因表达关系的研究进行了总结,同时对组蛋白修饰组合模式一些适用的研究方法做了概述和分析.     

Binary switches and modification cassettes in histone biology and beyond

An immense number of post-translational modifications on histone proteins have been described and additional sites of modification are still being uncovered. Whereas many direct and indirect connections between certain histone modifications and distinct biological phenomena have now been established, concepts for comprehending the extreme density and variety of these covalent modifications are lacking. Here, we formally introduce localized 'binary switches' and 'modification cassettes' as new concepts in histone biology, elucidating mechanisms that might govern the biological readout of distinct modification patterns. Specifically, our hypotheses provide missing models for the dynamic readout of stable histone modifications and offer explanations for several long-standing questions embedded in the literature. Our ideas might also apply to non-histone proteins and are open to direct experimental examination.     

Multifunctions of histone H1 proteins

Among various histones, histone H1 proteins have been appreciated for their multiple functions in diverse biological processes. In addition to being a structural protein in chromatin, H1 proteins also play critical roles in cell cycle, gene expression, and development. Recent studies reveal the possible effects of H1 in some diseases, such as cancer and neurodegenerative diseases. Here, we review different variants of HI, the functions, and post translational modifications of ill variants are also discussed.     

基于广义线性模型的基因表达水平预测

组蛋白修饰是生物体中普遍存在的一种现象,能够以不同的调控方式影响基因表达,且随着高通量测序技术的飞速发展,大量的测序数据使得探究组蛋白修饰信号与基因表达水平之间的内在联系成为可能.由于基因表达数据存在零膨胀现象,提出了一种基于广义线性模型框架的主从模型,能够以较高精度从组蛋白修饰信号预测基因表达水平.首先通过人类全基因组注释文件中的基因位点信息,筛选出包含完整基因位点信息的表达数据;其次,根据基因位点信息,定位并提取出组蛋白修饰数据中基因特定位点的特征信息,构建设计矩阵;最后结合响应变量数据零膨胀的特点,构建主从模型,以GM12878细胞系为例,与现有的多种回归算法进行对比,验证了所提模型的有效性.     

Recovery of learning and memory is associated with chromatin remodelling

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.     

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation

Numerous post-translational modifications of histones have been described in organisms ranging from yeast to humans. Growing evidence for dynamic regulation of these modifications, position- and modification-specific protein interactions, and biochemical crosstalk between modifications has strengthened the 'histone code' hypothesis, in which histone modifications are integral to choreographing the expression of the genome. One such modification, ubiquitylation of histone H2B (uH2B) on lysine 120 (K120) in humans, and lysine 123 in yeast, has been correlated with enhanced methylation of lysine 79 (K79) of histone H3 (refs 5-8), by K79-specific methyltransferase Dot1 (KMT4). However, the specific function of uH2B in this crosstalk pathway is not understood. Here we demonstrate, using chemically ubiquitylated H2B, a direct stimulation of hDot1L-mediated intranucleosomal methylation of H3 K79. Two traceless orthogonal expressed protein ligation (EPL) reactions were used to ubiquitylate H2B site-specifically. This strategy, using a photolytic ligation auxiliary and a desulphurization reaction, should be generally applicable to the chemical ubiquitylation of other proteins. Reconstitution of our uH2B into chemically defined nucleosomes, followed by biochemical analysis, revealed that uH2B directly activates methylation of H3 K79 by hDot1L. This effect is mediated through the catalytic domain of hDot1L, most likely through allosteric mechanisms. Furthermore, asymmetric incorporation of uH2B into dinucleosomes showed that the enhancement of methylation was limited to nucleosomes bearing uH2B. This work demonstrates a direct biochemical crosstalk between two modifications on separate histone proteins within a nucleosome.