DNA甲基化异常与垂体腺瘤研究进展

DNA甲基化是已知的哺乳动物DNA唯一的自然化学修饰方式,与基因表达调控、染色体稳定性及细胞分化有关,在肿瘤的发生过程中起着重要的调节作用。DNA甲基化异常可发生在多数人类肿瘤及癌前病变中,其主要在转录水平抑制基因的表达。垂体腺瘤是颅内常见的一种良性肿瘤,发病机制尚不完全清楚,近年研究表明DNA异常甲基化与垂体腺瘤发生关系密切,本文综述了DNA甲基化的现状、DNA异常甲基化在肿瘤发生中的作用、垂体腺瘤相关基因异常甲基化模式和基因表达的关系及去甲基化对垂体肿瘤治疗的应用前景和意义。     

DNA甲基化与高同型半胱氨酸血症

DNA甲基化是一种调控基因表达的表观遗传机制,由Hcy代谢相关底物S-腺苷同型半胱氨酸（S-adenosyl-L-homocysteine,SAH）依赖性的DNA甲基转移酶（DNA methyltransferases,DNMTs）催化,对维持细胞稳态至关重要。多项研究表明,高同型半胱氨酸血症（hyperhomocysteinemia,HHcy）可能通过调节甲硫氨酸-同型半胱氨酸循环（methionine-homocysteine cycle,M-H cycle）调控DNA甲基化状态,参与动脉粥样硬化形成过程中的血管内皮细胞功能障碍、损伤后平滑肌细胞（smooth muscle cells,SMCs）的增殖和转移、脂质代谢等病理过程,从而影响心血管疾病的发生和预后。     

DNA甲基化与脑肿瘤

随着人类对肿瘤研究的日益深入,许多学者已经清楚地认识到,肿瘤的发生、发展不仅与细胞内基因突变、缺失等因核苷酸序列改变所导致的遗传调控紊乱有关,还与表观遗传调控异常有着密切的联系[1].所谓表观遗传,是指通过DNA甲基化、组蛋白乙酰化和甲基化、染色质构型变化等所导致的在基因表达水平的改变.它只影响基因的转录活性而不影响核苷酸序列的改变[2].其中,DNA甲基化作为常见的表观遗传学修饰模式,在哺乳动物基因表达调控中起着重要的作用.异常甲基化可导致癌基冈的活化、非必需重复序列的转录、抑癌基因及DNA修复基因的沉默等,并能以半保留的方式高保真地传递到子代细胞的基岗组中,最终引发肿瘤[1].     

DNA甲基化在阿尔茨海默病发病机制中作用的研究新进展

DNA甲基化是表观遗传学中最稳定、最重要的一种修饰方式,可调控基因表达,从而产生生物学效应,其异常会导致多种疾病.阿尔茨海默病(Alzheimer disease,AD)是最常见的神经退行性病变之一,但其病理机制尚不明确,治疗及诊断方法有限.最近研究表明,表观遗传学,尤其是DNA甲基化在AD发病过程中发挥了重要作用.现...     

物质成瘾的组蛋白修饰研究进展

物质成瘾是一种以病理性学习记忆为基础的慢性复发性脑病。成瘾物质所致基因表达水平持续改变是成瘾行为产生和维持的基础。表观遗传作为一种介导环境与机体相互作用的中间机制调控着成瘾物质所致的相关基因表达水平的改变。组蛋白修饰,包括组蛋白乙酰化、磷酸化和甲基化等能被成瘾物质调控;并影响成瘾相关行为的形成。本文主要对组蛋白修饰的研究方法和近年来物质成瘾的组蛋白修饰的相关研究进行回顾。     

DNA甲基化异常与垂体瘤

近年来,DNA甲基化的研究进展迅速,去甲基化治疗已成为可能。章综述了DNA甲基化的研究现状,垂体瘤相关基因的异常甲基化模式与基因表达的关系以及DNA甲基化研究在垂体瘤治疗中的意义。     

母爱剥夺对成年大鼠行为及多巴胺受体2基因表达的影响

目的 研究母爱剥夺对大鼠脑伏隔核多巴胺受体2(DRD2)基因表达的影响,探索DNA甲基化是否参与调控DRD2基因的表达.方法 20只新牛大鼠被随机分为母爱剥夺组(8只)和对照组(12只),母爱剥夺组大鼠于哺乳期每天接受6 h母爱剥夺;12周龄时,采用旷场试验评估大鼠的焦虑水平和探索能力,并采用逆转录聚合酶链反应检测伏隔核DRD2受体mRNA表达水平,用亚硫酸测序法检测DRD2基因启动子区DNA甲基化水平.结果 (1)母爱剥夺组爬行总格数[(24 ±8)个]和直立次数[(10.1±2.0)次]少于对照组[分别为(44±8)个,(15.8±1.8)次;t=-5.12和-2.11,P<0.01～0.05].(2)母爱剥夺组大鼠脑内伏隔核DRD2 mRNA表达(0.224±0.064)低于对照组(0.587 ±0.099;t=-7.50,P<0.05);两组DRD2基因启动子区的DNA甲基化水平差异无统计学意义(P>0.05).结论 母爱剥夺大鼠成年以后在新奇环境中的焦虑水平增加,探索能力下降;母爱剥夺影响大鼠多巴胺系统DRD2基因表达,而DNA甲基化不参与调控基因表达.     

物质成瘾的表观遗传机制

<正>表观遗传(epigenetic)是指在基因DNA序列没有发生改变的情况下,基因表达发生可遗传的改变,并最终导致可遗传的表型变化,而且这种改变在个体发育和细胞增殖过程中能稳定遗传并具有可逆潜能。表观遗传包括DNA甲基化、组蛋白修饰、非编码RNA调控等。表观遗传参与大脑分化与发育,越来越多证据表明,表观遗传机制参与精神分裂症、双相情感障碍、物质成瘾、孤独症等精神障碍     

胶质瘤的DNA甲基化研究新进展

DNA甲基化主要指DNA的5'-胞嘧啶甲基化,是真核生物DNA的一种最常见的修饰方式,也是一种重要的表遗传学机制.近年来,DNA甲基化与胶质瘤相关性研究表明,许多肿瘤相关基因启动子区域CpG岛高甲基化与胶质瘤的形成关系密切.     

中枢学习记忆功能相关基因

近几年随着遗传学和分子生物学等技术的迅速发展,使我们从基因水平对构成学习记忆基础的分子机制有了进一步的认识.这些研究表明,学习记忆过程所必需的许多分子和分子机制在进化过程中得到保存,多种基因及其产物可在细胞膜受体、胞质内信号转导通路级联成分、胞核内基因表达的转录调节以及细胞生长发育等多个层次与学习记忆的调控有关.本文仅就来自海兔、果蝇和啮齿类动物的与中枢学习记忆功能有关的基因进行综述.     

Role of DNA methylation and the DNA methyltransferases in learning and memory

Dynamic regulation of chromatin structure in postmitotic neurons plays an important role in learning and memory. Methylation of cytosine nucleotides has historically been considered the strongest and least modifiable of epigenetic marks. Accumulating recent data suggest that rapid and dynamic methylation and demethylation of specific genes in the brain may play a fundamental role in learning, memory formation, and behavioral plasticity. The current review focuses on the emergence of data that support the role of DNA methylation and demethylation, and its molecular mediators in memory formation.     

Physical exercise as an epigenetic modulator of brain plasticity and cognition

A large amount of evidence has demonstrated the power of exercise to support cognitive function, the effects of which can last for considerable time. An emerging line of scientific evidence indicates that the effects of exercise are longer lasting than previously thought up to the point to affect future generations. The action of exercise on epigenetic regulation of gene expression seem central to building an “epigenetic memory” to influence long-term brain function and behavior. In this review article, we discuss new developments in the epigenetic field connecting exercise with changes in cognitive function, including DNA methylation, histone modifications and microRNAs (miRNAs). The understanding of how exercise promotes long-term cognitive effects is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.     

Stress, epigenetic control of gene expression and memory formation

Making memories of a stressful life event is essential for an organism's survival as it allows it to adapt and respond in a more appropriate manner should the situation occur again. However, it may be envisaged that extremely stressful events can lead to formation of traumatic memories that are detrimental to the organism and lead to psychiatric disorders such as post-traumatic stress disorder (PTSD). The neurotransmitter glutamate and the ERK MAPK signaling pathway play a principal role in learning and memory. Glucocorticoid hormones acting via the glucocorticoid receptor have been shown to strengthen the consolidation of memories of stressful events. The ERK MAPK signaling pathway and glucocorticoid receptor-mediated actions have recently been shown to drive epigenetic modifications and conformational changes in the chromatin, stimulating the expression of neuroplasticity-related genes involved in stress-related learning and memory processes. The main epigenetic regulatory mechanisms are histone modifications and DNA (de-)methylation. Recently, studies have demonstrated that these processes are acting together in concert to regulate gene expression required for memory consolidation. This review explores the role of stress in learning and memory paradigms and the participating signaling pathways and epigenetic mechanisms and the enzymes that control these modifications during the consolidation process of memory formation.     

Epigenetic perspective on the developmental effects of bisphenol A

Bisphenol A (BPA) is an estrogenic environmental toxin widely used in the production of plastics and ubiquitous human exposure to this chemical has been proposed to be a potential risk to public health. Animal studies suggest that in utero and early postnatal exposure to this compound may produce a broad range of adverse effects, including impaired brain development, sexual differentiation, behavior, and immune function, which could extend to future generations. Molecular mechanisms that underlie the long-lasting effects of BPA continue to be elucidated, and likely involve disruption of epigenetic programming of gene expression during development. Several studies have provided evidence that maternal exposure to BPA results in postnatal changes in DNA methylation status and altered expression of specific genes in offspring. However, further studies are needed to extend these initial findings to other genes in different tissues, and to examine the correlations between BPA-induced epigenetic alterations, changes in gene expression, and various phenotypic outcomes. It will be also important to explore whether the epigenetic effects of BPA are related to its estrogenic activity, and to determine which downstream effector proteins could mediate changes in DNA methylation. In this review, we will highlight research indicating a consequence of prenatal BPA exposure for brain, behavior, and immune outcomes and discuss evidence for the role of epigenetic pathways in shaping these developmental effects. Based on this evidence, we will suggest future directions in the study of BPA-induced epigenetic effects and discuss the transgenerational implications of exposure to endocrine disrupting chemicals.     

DNA Modifications and Neurological Disorders

Mounting evidence has recently underscored the importance of DNA methylation in normal brain functions. DNA methylation machineries are responsible for dynamic regulation of methylation patterns in discrete brain regions. In addition to methylation of cytosines in genomic DNA (5-methylcytosine; 5mC), other forms of modified cytosines, such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, can potentially act as epigenetic marks that regulate gene expression. Importantly, epigenetic modifications require cognate binding proteins to read and translate information into gene expression regulation. Abnormal or incorrect interpretation of DNA methylation patterns can cause devastating consequences, including mental illnesses and neurological disorders. Although DNA methylation was generally considered to be a stable epigenetic mark in post-mitotic cells, recent studies have revealed dynamic DNA modifications in neurons. Such reversibility of 5mC sheds light on potential mechanisms underlying some neurological disorders and suggests a new route to correct aberrant methylation patterns associated with these disorders.     

Emerging role of epigenetics in stroke: part 1: DNA methylation and chromatin modifications

Epigenetic mechanisms refer to the complex and interrelated molecular processes that dynamically modulate gene expression and function within every cell in the body. These regulatory systems represent the long-sought-after molecular interfaces that mediate gene?×?environment interactions. Changes in the epigenome throughout life are responsible not only for controlling normal development, adult homeostasis, and aging but also for mediating responses to injury. Emerging evidence implicates a spectrum of epigenetic processes in the pathophysiology of stroke. In this review, we describe conventional epigenetic mechanisms (including DNA methylation, histone code modifications, nucleosome remodeling, and higher-order chromatin formation) and highlight the emerging roles each of these processes play in the pathobiology of stroke. We suggest that understanding these mechanisms may be important for discovering more sensitive and specific biomarkers for risk, onset, and progression of stroke. In addition, we highlight epigenetic approaches for stroke therapy, including the inhibition of DNA methyltransferase and histone deacetylase enzyme activities. These therapeutic approaches are still in their infancy, but preliminary results suggest that contemporary agents targeting these pathways can regulate the deployment of stress responses that modulate neural cell viability and promote brain repair and functional reorganization. Indeed, these agents even appear to orchestrate sophisticated cognitive functions, including learning and memory.