DNA甲基化及组蛋白修饰在精神分裂症中的改变

精神分裂症（schizophrellia）是一种严重的精神疾病,对双胞胎、家庭及认养的研究揭示,遗传与环境因素之间复杂的相互作用是精神分裂症的病因。表观遗传学（epigenetics）研究与基因序列变化无关的基因表达调控机制．为人们深入认识精神分裂症的病因提供了新的思路。表观遗传调控机制主要包括：DNA甲基化、组蛋白修饰和非编码RNA三种方式。该文介绍前两种在精神分裂症发病机制中的作用。     

DNA甲基化与组蛋白修饰对克隆胚发育的影响

在正常的受精、发育过程中,基因组DNA不对称的去甲基化、重新甲基化以及组蛋白修饰作用发生在整个受精和胚胎发育过程中。本文将从DNA甲基化、DNA不对称的去甲基化和组蛋白修饰作用就其原理,相互之间的关系及其对胚胎发育情况的影响作以综述,并对近年来,DNA甲基化与组蛋白修饰作用在胚胎发育过程中的研究作以总结。     

基因组DNA甲基化修饰在胚胎干细胞分化过程中的作用

基因组DNA的甲基化修饰通常使基因转录失活,去甲基化或低甲基化则使基因转录活化。但是,胚胎干细胞向各种成体细胞分化过程中相关基因的转录活化与DNA甲基化修饰水平并不呈简单的正性或负性相关。因此,甲基化修饰调节基因转录是一个复杂的过程。目前,对甲基化修饰作用的研究主要集中在基因选择性活化、改变转录因子与靶基因的结合活性、与组蛋白修饰协同作用及其基因表达的阶段特异性等方面。     

哺乳动物卵泡发育过程中组蛋白甲基化修饰的研究进展

卵泡的正常发育涉及有序的基因转录激活和抑制等一系列复杂的生命过程,对雌性获得生殖能力至关重要.组蛋白甲基化修饰可以改变细胞内染色质的状态,影响基因的转录活性.现阶段的研究表明,组蛋白甲基化等表观遗传学修饰在雌性哺乳动物卵泡发育的过程中发挥了重要的调控作用.本文总结了组蛋白赖氨酸甲基化(H3K4及H3K9)等甲基化修饰与...     

表观遗传修饰在作物重要性状形成中的作用

表观遗传修饰是指染色体DNA和组蛋白上的化学修饰,主要包括DNA甲基化、组蛋白修饰和非编码RNA.在不改变DNA序列的情况下,这些修饰可以通过改变染色质状态来影响遗传信息的表达,并具有可遗传性,对植物的生长发育具有重要的调控作用.当特定的表观遗传修饰发生改变时,农作物可以获得优异的表型、更强的环境适应性,因此人为改变表...     

组蛋白甲基化修饰效应分子的研究进展

作为一种重要的表观遗传学调控机制,组蛋白甲基化修饰在多种生命过程中发挥了重要的作用。细胞内有多种组蛋白甲基化酶和去甲基化酶共同调节组蛋白的修饰状态,在组蛋白甲基化状态确定后,多种效应分子特异的读取修饰信息,从而参与基因转录调控过程。文章从组蛋白甲基化效应分子的作用机制方面综述了这一领域的研究进展。     

精子发生过程中组蛋白甲基化和乙酰化

精子发生(Spermatogenesis)这一高度复杂的独特分化过程包括精原细胞发育为精母细胞、单倍体精细胞的形成和精子成熟,并以阶段特异性和睾丸特异性基因的表达、有丝分裂和减数分裂以及组蛋白向鱼精蛋白的转变为特征。表观遗传修饰在减数分裂重组、联会复合物的形成、姊妹染色体的结合、减数分裂后精子的变态、基因表达阻遏和异染色质形成过程中发挥着重要作用。其中具有一定组成形式、起抑制作用和/或激活作用的组蛋白甲基化和乙酰化标记,不仅保证了正确的染色体配对和二价染色体的成功分离,并且精确调节减数分裂特异性基因的适时表达。精子发生过程中组蛋白甲基化和/或乙酰化错误会直接影响表观遗传修饰的建立和维持,导致生精细胞异常甚至引发不育。文章旨在对精子发生过程中组蛋白甲基化和乙酰化表观遗传修饰的动态变化及其相关酶的调节机制进行综述,为进一步研究精子发生的表观遗传调控,预防男性不育疾病的发生提供基础资料。     

DNA甲基化修饰与体细胞核移植的关系

成功的体细胞核移植（somatic cell nuclear transfer,SCNT）有赖于供体细胞的基因组通过重编程恢复到支持胚胎发育的全能性状态。但是,相比起自然受精后发生的重编程来说,要诱导一个已经分化的供体细胞重编程为全能性状态,往往在时间上和程度上都是迟滞的和不完全的。同时,DNA甲基化状况又是影响克隆胚胎发育和基因表达的关键因素之一。因此,深入研究主导DNA甲基化修饰的分子机理,探讨DNA去甲基化在供体细胞重编程过程中扮演的角色,从而进一步提高供体细胞重编程效率,提高克隆胚的发育潜能,这对于体细胞核移植效率的提高具有重要的意义。     

组蛋白乙酰化、DNA甲基化在肿瘤发生中的作用

组蛋白乙酰化和DNA甲基化调控基因表达的两种主要方式,目前认为组蛋白乙酰化和DNA低甲基化可促进基因表达,而组蛋白去乙酰化和DNA高甲基化可抑制基因表达,组蛋白乙酰化和DNA甲基化这两种分子机制相互协调,实现基因表达的精细调控。     

组蛋白修饰在先天性心脏病中的作用（英文）

先天性心脏病(congenital heart disease, CHD)是包括心肌壁、瓣膜和主要血管缺陷在内的心脏先天性结构异常疾病。虽然胚胎发生过程中的基因突变和异常基因表达等遗传因素会导致CHD,但这些只能解释一部分CHD的发病原因。表观遗传中的组蛋白修饰在CHD中的研究越来越多,提示其在CHD发病机制中愈发重要。随着基于质谱的蛋白质组学技术发展,一系列新型组蛋白翻译后修饰,包括琥珀酰化、糖基化、乳酸化和β-羟基丁酰化等在疾病中发挥的作用被揭示,而这些新型修饰如何调控CHD的发生发展过程中的基因表达以及病理进程并不得知。本文将分别从经典组蛋白修饰和新型组蛋白修饰出发阐述不同的组蛋白修饰参与调控心脏发育基因的作用机制,以期揭示组蛋白驱动的表观遗传机制在CHD病因学中的重要性,也为CHD的临床治疗及时预防提供理论依据。     

DNA甲基化与克隆动物的发育异常

通过核移植技术得到的大多数克隆动物在出生前就已经死亡, 只有极少数可以发育至妊娠期末或者存活至成年, 即使是存活下来的克隆动物也伴有不同程度的发育缺陷和表型异常。DNA甲基化是支配基因正常表达的一种重要的表观遗传修饰方式, 是调节基因组功能的重要手段, 在胚胎的正常发育过程中具有显著作用。通过对DNA甲基化模式的研究, 人们发现克隆动物中存在着异常的DNA甲基化状态, 而这些异常的DNA甲基化模式可能就是导致克隆胚早期死亡以及克隆动物发育畸形的主要原因。文章主要论述了DNA甲基化的作用, 克隆动物中异常的DNA甲基化模式, 以及造成克隆胚胎甲基化异常的原因等问题。     

Aberrant DNA methylation in 5'regions of DNA methyltransferase genes in aborted bovine clones

High rate of abortion and developmental abnormalities is thought to be closely associated with inefficient epigenetic reprogramming of the transplanted nuclei during bovine cloning.It is known that one of the important mechanisms for epigenetic reprogramming is DNA methylation.DNA methylation is established and maintained by DNA methyltransferases(DNMTs),therefore,it is postulated that the inefficient epigenetic reprogramming of transplanted nuclei may be due to abnormal expression of DNMTs.Since DNA methylation can strongly inhibit gene expression,aberrant DNA methylation of DNMT genes may disturb gene expression.But presently,it is not clear whether the methylation abnormality of DNMT genes is related to developmental failure of somatic cell nuclear transfer embryos.In our study,we analyzed methylation patterns of the 5' regions of four DNMT genes including Dnmt3a,Dnmt3b,Dnmtl and Dnmt2 in four aborted bovine clones.Using bisulfite sequencing method,we found that 3 out of 4 aborted bovine clones(AF1,AF2 and AF3)showed either hypermethylation or hypomethylation in the 5' regions of Dnmt3a and Dnmt3b.indicating that Dnmt3a and Dnmt3b genes are not properly reprogrammed.However,the individual AF4 exhibited similar methylation level and pattern to age-matched in vitro fertilized (IVF)fetuses.Besides,we found that tle 5'regions of Dnmtl and Dnmt2 were nearly completely unmethylated in all normal adults.IVF fetuses,sperm and aborted clones.Together,our results suggest that the aberrant methylation of Dnmt3a and Dnmt3b 5' regions is probably associated with the high abortion of bovine clones.     

Aberrant DNA methylation imprints in aborted bovine clones

Genomic imprinting plays a very important role during development and its abnormality may heavily undermine the developmental potential of bovine embryos. Because of limited resources of the cow genome, bovine genomic imprinting, both in normal development and in somatic cell nuclear transfer (SCNT) cloning, is not well documented. DNA methylation is thought to be a major factor for the establishment of genomic imprinting. In our study, we determined the methylation status of differential methylated regions (DMRs) of four imprinted genes in four spontaneously aborted SCNT-cloned fetuses (AF). Firstly, abnormal methylation imprints were observed in each individual to different extents. In particular, Peg3 and MAOA were either seriously demethylated or showed aberrant methylation patterns in four aborted clones we tested, but Xist and Peg10 exhibited relatively better maintained methylation status in AF1 and AF4. Secondly, two aborted fetuses, AF2 and AF3 exhibited severe aberrant methylation imprints of four imprinted genes. Finally, MAOA showed strong heterogeneous methylation patterns of its DMR in normal somatic adult tissue, but largely variable methylation levels and relatively homogeneous methylation patterns in aborted cloned fetuses. Our data indicate that the aborted cloned fetuses exhibited abnormal methylation imprints, to different extent, in aborted clones, which partially account for the higher abortion and developmental abnormalities during bovine cloning.     

Regulation beyond genome sequences: DNA and histone methylation in embryonic stem cells

Embryonic stem (ES) cells distinct themselves from other cell type populations by their pluripotent ability. The unique features of ES cells are controlled by both genetic and epigenetic factors. Studies have shown that the methylation status of DNA and histones in ES cells is quite different from that of differentiated cells and somatic stem cells. Herein, we summarized recent advances in DNA and histone methylation studies of mammalian ES cells. The methylation status of several key pluripotent regulatory genes is also discussed.     

Epigenetic regulation: methylation of histone and non-histone proteins

Histone methylation is believed to play important roles in epigenetic memory in various biological processes. However, questions like whether the methylation marks themselves are faithfully transmitted into daughter cells and through what mechanisms are currently under active investigation. Previously, methylation was considered to be irreversible, but the recent discovery of histone lysine demethylases revealed a dynamic nature of histone methylation regulation on four of the main sites of methylation on histone H3 and H4 tails (H3K4, H3K9, H3K27 and H3K36). Even so, it is still unclear whether demethylases specific for the remaining two sites, H3K79 and H4K20, exist. Furthermore, besides histone proteins, the lysine methylation and demethylation also occur on non-histone proteins, which are probably subjected to similar regulation as histones. This review discusses recent progresses in protein lysine methylation regulation focusing on the above topics, while referring readers to a number of recent reviews for the biochemistry and biology of these enzymes     

表观遗传修饰在调控寿命中的作用

表观遗传修饰是生命现象中普遍存在的一类基因调控方式,主要包括DNA甲基化、组蛋白乙酰化和组蛋白甲基化等,通常协同调控基因表达。端粒是位于真核生物染色体末端的保护性结构,在端粒以及亚端粒区域中也存在丰富的表观遗传修饰。随着研究深入,发现表观遗传修饰在调控寿命过程中扮演着重要角色,而揭示衰老的有关机制有助于我们找到延长寿命的方法,具有重大的生物学意义和临床应用前景。     

Symmetrical modification within a nucleosome is not required globally for histone lysine methylation

Two copies of each core histone exist in every nucleosome; however, it is not known whether both histones within a nucleosome are required to be symmetrically methylated at the same lysine residues. We report that for most lysine methylation states, wild-type histones paired with mutant, unmethylatable histones in mononucleosomes have comparable methylation levels to bulk histones. Our results indicate that symmetrical histone methylation is not required on a global scale. However, wild-type H4 histones paired with unmethylatable H4K20R histones showed reduced levels of H4K20me2 and H4K20me3, suggesting that some fractions of these modifications might exist symmetrically, and enzymes mediating these modifications might, to some extent, favour nucleosome substrates with premethylated H4K20.