重性抑郁障碍发病的表观遗传调控假说

表观遗传学是研究主要受控于DNA甲基化、染色质结构变化的可遗传和逆转的基因组功能的调控。近年来, 越来越多的证据表明表观遗传因素在精神分裂症、双相障碍、药物成瘾等重性精神障碍的发病中扮演着重要角色。文章综述了表观遗传现象的分子机制, 介绍了表观遗传修饰与复杂性疾病的关系, 并在此基础上对重性抑郁障碍(Major depressive disorder, MDD)发病的表观遗传调控假说及最新研究进展进行了总结。     

上皮细胞转分化及其表观遗传学调控

上皮细胞转分化现象及其与疾病发生发展的关系,近年已成为细胞生物学、免疫学等多学科关注的聚焦点。转分化作为细胞分化发育的基本生物学现象,存在于机体诸多生理病理过程,也受表观遗传学的调控。相对于经典遗传学而言,表观遗传学作为一门新兴学科,其为生物体的基因表达调控及遗传现象提供了新的理论阐释。现知,DNA甲基化、组蛋白修饰及非编码RNA等均可导致上皮细胞基因发生表观遗传改变,与上皮细胞转分化的发生发展密切相关,并在该过程中发挥重要的调控作用。进一步阐明细胞转分化的分子基础及其表观遗传学调控机制,将有助于认识生命现象基本过程,并可为炎症性疾病、自身免疫病、器官纤维化,以及肿瘤发生与转移等机制的研究与防治,提供新的思路和应对策略。对上皮细胞转分化与表观遗传学调控关系作一简述。     

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。     

植物DNA甲基化及其表观遗传作用

表观遗传学(epigenetics)是研究没有DNA序列变化的、可遗传的基因表达的改变。目前研究表明,表观遗传学在植物生长发育过程中起着极其重要的作用,主要通过包括DNA甲基化、RNA干涉、基因组印记、转基因沉默等多个方面来调控植物的生长发育。其中,DNA甲基化是表观遗传学的最重要研究内容之一,是调节基因组功能的重要手段。现对植物DNA甲基化的特征、维持机制、调控机制、表观遗传作用及其研究方法进行简要论述。     

组蛋白修饰调节机制的研究进展

表观遗传学涉及到DNA甲基化、组蛋白修饰、染色体重塑和非编码RNA调控等内容,其中组蛋白修饰包括组蛋白的乙酰化、磷酸化、甲基化、泛素化及ADP核糖基化等,这些多样化的修饰以及它们时间和空间上的组合与生物学功能的关系又可作为一种重要的表观标志或语言,因而被称为“组蛋白密码”．相同组蛋白残基的磷酸化与去磷酸化、乙酰化与去乙酰化、甲基化与去甲基化等,以及不同组蛋白残基的磷酸化与乙酰化、泛素化与甲基化、磷酸化与甲基化等组蛋白修 饰之间既相互协同又互相拮抗,形成了一个复杂的调节网络．对组蛋白修饰内在调节机制的研究将丰富“组蛋白密码”的内涵．     

表观遗传学: 生物细胞非编码RNA调控的研究进展

表观遗传学是研究基因表达发生了可遗传的改变, 而DNA序列不发生改变的一门生物学分支, 对细胞的生长分化及肿瘤的发生发展至关重要。表观遗传学的主要机制包括DNA甲基化、组蛋白修饰及新近发现的非编码RNA。非编码RNA 是指不能翻译为蛋白的功能性RNA分子, 其中常见的具调控作用的非编码RNA包括小干涉RNA、miRNA、piRNA 以及长链非编码RNA。近年来大量研究表明非编码RNA在表观遗传学的调控中扮演了越来越重要的角色。文章综述了近年来生物细胞非编码RNA调控的表观遗传学研究进展, 以有助于理解哺乳动物细胞中非编码RNA及其调控机制和功能。     

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。     

神经退行性疾病的表观遗传学

研究发现多种疾病的发生与表观遗传学相关.有证据显示表观遗传学信号在大脑中起着重要调节作用,在哺乳动物中枢神经系统中DNA甲基化动力学被发现是表观遗传学调节的主要组成,染色质修饰药物的快速发展显示出对神经系统中范围广泛的退行性功能紊乱出人意料的治疗作用,促进了人们对神经退行性疾病的表观遗传学机制研究.其中,研究得比较多的是DNA甲基化、组蛋白修饰及染色质重塑.这些研究为神经退行性疾病的治疗提供了潜在靶点,并为开发相关药物提供了线索.对疾病表观遗传学机制及药物的作用机制的进一步研究将为疾病治疗提供更多靶点,为神经退行性疾病提供确切的有效治疗途径,具有积极意义.     

表观遗传学及其研究方法

表观遗传学是一门重要的生命学科,主要包括DNA的甲基化、组蛋白修饰以及非编码RNA等内容,其中任何一方面的表观遗传学变化对生物体的生命过程都有重要的影响。近年来随着生命科学的快速发展,表观遗传学越来越受到人们的关注,各种先进科技的应用也使得表观遗传学实验技术得到快速的发展。本文对DNA甲基化、组蛋白修饰及非编码RNA的基本内容及实验方法进行了综述,并对不同的研究方法进行分析,有利于表观遗传学的深入研究。     

表观遗传学及现代表观遗传生物医药技术的发展北大核心CSCD

表观遗传学和基于表观遗传机制的生物医药技术的研究已经成为后基因组时代生命科学技术领域的重要组成部分。围绕肿瘤、心脑血管疾病、糖尿病及中老年神经退行性疾病等过程中DNA甲基化修饰、组蛋白翻译后修饰及非编码RNA等表观遗传学改变的深入研究,不仅有利于理解相关疾病的分子病理机制,而且,更有助于探寻基于表观遗传机制的有效治疗手段。在阐释表观遗传学修饰机制的基础上,对疾病过程中异常的表观遗传学修饰及相关生物医药技术的研究现状进行了归纳总结。     

CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication.

The physical parameters controlling the accessibility of antigen receptor loci to the V(D)J recombination activity are unknown. We have used minichromosome substrates to study the role that CpG methylation might play in controlling V(D)J recombination site accessibility. We find that CpG methylation decreases the V(D)J recombination of these substrates more than 100-fold. The decrease correlates with a considerable increase in resistance to endonuclease digestion of the methylated minichromosome DNA. The minichromosomes acquire resistance to both the intracellular V(D)J recombinase and exogenous endonuclease only after DNA replication. Therefore, CpG methylation specifies a chromatin structure that, upon DNA replication, is resistant to eukaryotic site-specific recombination. These findings are important to V(D)J recombination as well as to the chromatin assembly of methylated DNA during replication.     

Histone acetylation and hSWI/SNF remodeling act in concert to stimulate V(D)J cleavage of nucleosomal DNA

The ordered assembly of immunoglobulin and TCR genes by V(D)J recombination depends on the regulated accessibility of individual loci. We show here that the histone tails and intrinsic nucleosome structure pose significant impediments to V(D)J cleavage. However, alterations to nucleosome structure via histone acetylation or by stable hSWI/SNF-dependent remodeling greatly increase the accessibility of nucleosomal DNA to V(D)J cleavage. Moreover, acetylation and hSWI/SNF remodeling can act in concert on an individual nucleosome to achieve levels of V(D)J cleavage approaching those observed on naked DNA. These results are consistent with a model in which regulated recruitment of chromatin modifying activities is involved in mediating the lineage and stage-specific control of V(D)J recombination.     

ATP-dependent remodeling by SWI/SNF and ISWI proteins stimulates V(D)J cleavage of 5 S arrays

Control of V(D)J recombination is critical for the generation of a fully developed immune repertoire. The molecular mechanisms underlying the regulation of antigen receptor gene assembly are beginning to be revealed. Here we studied the influence of chromatin modifications on V(D)J cleavage of a polynucleosomal substrate, in which V(D)J cleavage is greatly reduced compared with naked DNA. ATP-dependent remodeling by human SWI/SNF (hSWI/SNF) in the presence of HMG1 led to a substantial increase of cleavage by the recombination activation gene (RAG) proteins. Either BRG1, the ATPase subunit of hSWI/SNF, or SNF2h, the ATPase of human ISWI complexes, was capable of stimulating V(D)J cleavage of the array, although these remodelers act by different mechanisms. No effect of histone hyperacetylation was detectable in this system. As is observed on naked DNA, in the presence of core RAG1, the full-length RAG2 protein proved to be more active than core RAG2 on these polynucleosomal arrays, reinforcing the importance of the RAG2 C-terminal domain for efficient recombination. Comparison of 5 S array cleavage by the RAG proteins or by the restriction enzyme HhaI after remodeling by hSWI/SNF suggested that RAG proteins and HhaI might have different requirements for maximal accessibility of the substrate.     

Chromatin remodeling at the Ig loci prior to V(D)J recombination.

Rearrangement of Ig H and L chain genes is highly regulated and takes place sequentially during B cell development. Several lines of evidence indicate that chromatin may modulate accessibility of the Ig loci for V(D)J recombination. In this study, we show that remodeling of V and J segment chromatin occurs before V(D)J recombination at the endogenous H and kappa L chain loci. In recombination-activating gene-deficient pro-B cells, there is a reorganization of nucleosomal structure over the H chain J(H) cluster and increased DNase I sensitivity of V(H) and J(H) segments. The pro-B/pre-B cell transition is marked by a decrease in the DNase I sensitivity of V(H) segments and a reciprocal increase in the nuclease sensitivity of Vkappa and Jkappa segments. In contrast, J(H) segments remain DNase I sensitive, and their nucleosomal organization is maintained in mu(+) recombination-activating gene-deficient pre-B cells. These results indicate that initiation of rearrangement is associated with changes in the chromatin structure of both V and J segments, whereas stopping recombination involves changes in only V segment chromatin. We further find an increase in histone H4 acetylation at both the H and kappa L chain loci at the pro-B cell stage. Although histone H4 acetylation appears to be an early change associated with B cell commitment, acetylation alone is not sufficient to promote subsequent modifications in Ig chromatin.     

Functional analysis of histone methyltransferase g9a in B and T lymphocytes

Lymphocyte development is controlled by dynamic repression and activation of gene expression. These developmental programs include the ordered, tissue-specific assembly of Ag receptor genes by V(D)J recombination. Changes in gene expression and the targeting of V(D)J recombination are largely controlled by patterns of epigenetic modifications imprinted on histones and DNA, which alter chromatin accessibility to nuclear factors. An important component of this epigenetic code is methylation of histone H3 at lysine 9 (H3K9me), which is catalyzed by histone methyltransferases and generally leads to gene repression. However, the function and genetic targets of H3K9 methyltransferases during lymphocyte development remain unknown. To elucidate the in vivo function of H3K9me, we generated mice lacking G9a, a major H3K9 histone methyltransferase, in lymphocytes. Surprisingly, lymphocyte development is unperturbed in G9a-deficient mice despite a significant loss of H3K9me2 in precursor B cells. G9a deficiency is manifest as modest defects in the proliferative capacity of mature B cells and their differentiation into plasma cells following stimulation with LPS and IL-4. Precursor lymphocytes from the mutant mice retain tissue- and stage-specific control over V(D)J recombination. However, G9a deficiency results in reduced usage of Iglambda L chains and a corresponding inhibition of Iglambda gene assembly in bone marrow precursors. These findings indicate that the H3K9me2 epigenetic mark affects a highly restricted set of processes during lymphocyte development and activation.