DNA甲基化与常见免疫性疾病

作为最常见的表观遗传修饰形式,DNA甲基化是调节基因组功能的重要机制。DNA甲基化的改变可以影响细胞因子等表达相关的基因,导致T细胞的分化及反应性发生改变,从而与免疫性疾病的发病机制密切相关。本文以系统性红斑狼疮和哮喘等常见免疫性疾病为例,重点阐述表观遗传学中DNA甲基化在免疫性疾病中的作用。     

DNA甲基化与人类糖尿病的研究进展

<正>2型糖尿病(T2DM)是多种环境因素和遗传因素共同作用的结果。近年来,在T2DM及其并发症发病机制的研究中发现,环境因素(如饮食)改变是引起T2DM发病的重要原因。环境因素可以直接影响基因的表型,而表观遗传学机制是疾病发生过程中介导环境因素和遗传因素之间相关性的分子桥梁。目前,对糖尿病表观遗传学机制中起重要作用的DNA甲基化的研究正如火如荼进行,主要是在全基因组扫描与糖尿病相关的DNA甲基化改变,或者是利用特异性引物检测某个已知功     

基因芯片检测甲基化在中老年食管鳞状细胞癌(ESCC)中的应用前景

<正>表观遗传学是目前生物学研究领域最具发展前景的学科〔1～4〕。基因自身的改变和表观遗传基因的改变都会通过复杂的信号转导,单独或共同的引起有害基因突变率的增加。表观遗传学通过几个机制控制基因的表达:DNA甲基化;组蛋白修饰;非编码RNA的表观遗传调控〔5,6〕。目前研究最广泛的是DNA甲基化〔7〕。实验表明DNA重复序列的甲基化,可能会导致细胞染色体缺失或重组,从而造成遗传不稳定。因此人类基     

DNA甲基化及其与动脉粥样硬化的关系

流行病学调查结果表明冠心病有明显的遗传倾向,其发病具有明显的家族聚集性。动脉粥样硬化是导致冠心病的主要因素,DNA甲基化是表观遗传学重要组成部分,调节特异性基因的表达,引起动脉粥样硬化,从而导致冠心病的发生。该文介绍了DNA甲基化及其在动脉粥样硬化的发生、发展方面的相关作用机制。     

CHD5基因在食管癌中的表观遗传学改变

目的:研究食管癌发病过程中染色质解旋酶DNA结合蛋白5(Chromodomain helicase DNA-binding protein5,CHD5)基因表观遗传学改变,探讨CHD5基因甲基化作为食管癌诊断标志物的可行性.方法:用甲基化特异性聚合酶链反应(methylation specific PCR,MSP)检测72例食管癌组织及成对癌旁组织,9例正常食管黏膜组织及4株食管癌细胞系中CHD5基因的甲基化状态,并用逆转录聚合酶链式反应(RT-PCR)检测CHD5基因在上述食管癌细胞系的表达.结果:69%(50/72)食管癌组织发生CHD5基因启动子区甲基化,32%(23/72)癌旁组织发生甲基化,差异具有统计学意义(χ2=20.254,P<0.05).9例食管正常组织未发生甲基化,2株食管癌细胞系中由于基因启动子区甲基化导致CHD5基因表达缺失,经5-aza-deoxycytidine处理96h后CHD5重新表达.结论:食管癌中CHD5基因频繁发生甲基化,表观遗传学改变是其基因表达的重要调节机制,CHD5基因甲基化有可能作为食管癌诊断的标志物.     

表观遗传调控在胰岛β细胞功能调控中的研究进展

表观遗传是指在DNA序列不发生改变情况下,基因表达发生可遗传性改变的现象.表观遗传在疾病发生发展中发挥重要作用,其机制十分复杂,包括DNA甲基化、组蛋白修饰和非编码RNA等.2型糖尿病是一种由遗传和环境因素共同作用而发生的复杂多基因遗传性疾病,其病因和发病机制目前尚未完全阐明.近年研究发现,表观遗传直接或间接调控胰岛β细胞的发育、分化、分泌功能以及机体对胰岛素的敏感性,参与2型糖尿病的发生和发展.对表观遗传调控的研究将为阐明2型糖尿病发病机制,及预防和治疗2型糖尿病提供新的思路和靶点.     

糖尿病肾脏病DNA甲基化的研究进展

糖尿病肾脏病(DKD)是糖尿病微血管并发症之一, 是导致终末期肾脏疾病的主要原因。DKD的发病机制除遗传易感基因因素以外还有环境因素, 而表观遗传学已被证明在遗传学和环境之间起桥梁作用。表观遗传学研究内容主要包括DNA甲基化、组蛋白翻译后修饰和非编码RNA调控。近年来, 国内外在DKD的DNA甲基化研究方面有长足发展, RNA甲基化研究也越来越引起关注。因此, 该文主要就目前DKD的DNA甲基化研究进行综述, 提出基于DNA甲基化研究可能的DKD诊断与治疗策略。     

DNA甲基化在高血压病中的研究进展

高血压病是由多个基因和环境因素共同作用的疾病,是全球最大的公共卫生健康问题之一。DNA甲基化是最早发现的表观遗传调控机制,在高血压的发生和发展中起着重要作用。与血压调节相关的基因启动子区域发生甲基化或去甲基化会影响相关酶和受体的表达,从而引起血压升高。深入探讨DNA甲基化在高血压病中的分子机制将为高血压的发病机制寻找新的科学依据。本文主要就DNA甲基化在高血压病发展中的表观遗传学机制进行综述。     

乳腺癌相关基因DNA甲基化的研究进展

乳腺癌是女性最常见的恶性肿瘤之一，严重威胁着妇女的健康。在乳腺癌发生过程中，除DNA序列改变外，表观遗传学改变在其形成过程中也具有重要作用。表观遗传学研究基因表达的变化，但不涉及DNA序列的改变。DNA甲基化是表观遗传学研究最深入的一种机制。DNA甲基化是指由DNA甲基转移酶（DNMT）催化，     

缺血性卒中DNA甲基化调控的研究进展

正神经可塑性作为贯穿于整个卒中后神经功能康复过程的基础[1],其发生机制目前并不十分清楚,但康复过程存在多种调控神经发育基因的改变。现代分子生物学研究显示,细胞中信息的表达受两种因素控制:一种是遗传调控,另一种是表观遗传调控。表观遗传学机制主要包括DNA甲基化/去甲基化,组蛋白修饰和非编码RNA(如microRNA),调控不同细胞类型的特异性基因表达及其转录程     

从DNA甲基化修饰角度探讨中医药干预冠心病的研究进展

冠心病是一种由多个基因及环境因素相互作用所致的常见复杂性疾病,近年来发现冠心病与DNA甲基化为代表的表观遗传修饰关系密切。表观遗传学研究的是环境而非遗传序列本身对基因表达的影响,这与中医整体观念、天人相应的理论不谋而合。中医遵循整体观念,重视环境等外部因素对人体的影响,通过治疗达到机体内在的平衡状态。近年来,中医科研工作者关于冠心病中医证候的DNA甲基化内涵,以及中药干预冠心病的甲基化机制方面的研究取得较大进展,笔者通过梳理相关文献并进行总结阐述,以期为未来研究提供参考。     

DNA methylation and microRNAs in cancer

DNA methylation is a type of epigenetic modification in the human genome, which means that gene expression is regulated without altering the DNA sequence. Methylation and the relationship between methylation and cancer have been the focus of molecular biology researches. Methylation represses gene expression and can influence embryogenesis and tumorigenesis. In different tissues and at different stages of life, the level of methylation of DNA varies, implying a fundamental but distinct role for methylation. When genes are repressed by abnormal methylation, the resulting effects can include instability of that gene and inactivation of a tumor suppressor gene. MicroRNAs have some aspects in common with this regulation of gene expression. Here we reviewed the influence of gene methylation on cancer and analyzed the methods used to profile methylation. We also assessed the correlation between methylation and other epigenetic modifications and microRNAs. About 55,845 research papers have been published about methylation, and one-fifth of these are about the appearance of methylation in cancer. We conclude that methylation does play a role in some cancer types.     

阻塞性睡眠呼吸暂停综合征与冠心病相关性的研究进展

阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome,OSAS)是一种发病率高、具有潜在危险性的疾病.近年研究显示OSAS与冠心病(coronary heart disease,CHD)关系密切,是CHD的独立危险因素,充分认识OSAS引起和促进CHD的发病机制,可以为OSAS相关CHD的防治提供重要的理论依据和新思路.     

Altered DNA methylation profile in idiopathic pulmonary fibrosis

Rationale: DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF). Objectives: To determine the DNA methylation changes in IPF and their effects on gene expression. Methods: Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels. Measurements and Main Results: DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression. Conclusions: Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.     

Detecting methylation patterns of p16, MGMT,DAPK and E-cadherin genes in multiple myeloma patients

Multiple myeloma (MM) is a B-cell neoplasia characterized by the clonal proliferation of plasma cells. Besides known genetic abnormalities, epigenetic changes are also known to effect MM pathogenesis. DNA methylation is an epigenetic mechanism that silences genes by adding methyl groups to cytosine-guanine dinucleotides at the promoter regions. In this study, the methylation status of four genes; p16, O6-methyl guanine DNA methyl transferase (MGMT), death-associated protein kinase (DAPK) and E-cadherin (ECAD); at the time of diagnosis was investigated using methylation-specific polymerase chain reaction (MS-PCR). In the 20 cases studied; methylation of the promoter regions of p16, MGMT, DAPK and ECAD genes was detected in 10%, 40%, 10% and 45% of the cases, respectively. In 65% (13/20) of cases, at least one of the genes studied had promoter methylation; while 35% of cases (7/20) had methylated promoters of more than one gene. There was a significant correlation between promoter hypermethylation of MGMT and the presence of extramedullary involvement; but for the other genes no correlation was found regarding disease properties like age, disease stage, clinical course and the presence of lytic bone lesions. Determining the methylation profiles of genes in MM, could lead to a new understanding of the disease pathogenesis and guide the assessment of treatment options.     

冠心病患者肺炎衣原体感染的临床实验研究

目的：了解冠心病患肺炎衣原体感染状况，探讨肺炎衣原体感染与冠心病发生发展的关系。方法：采用PCR技术对16l例经冠状动脉造影证实的冠心病患和4l例非冠心病思进行肺炎衣原体DNA检测。结果：冠心病组肺炎衣原体DNA阳性率为44．17％，非冠心病组阳性率为7．32％，前阳性率非常显高于后(P＜0．01)。结论：肺炎衣原体感染与冠心病存在一定的关系。     

LINE-1 Hypomethylation is Associated with the Risk of Coronary Heart Disease in Chinese Population

Background

Global methylation level in blood leukocyte DNA has been associated with the risk of coronary heart disease (CHD), with inconsistent results in various populations. Similar data are lacking in Chinese population where different genetic, lifestyle and environmental factors may affect DNA methylation and its risk relationship with CHD.

Objectives

To examine whether global methylation is associated with the risk of CHD in Chinese population.

Methods

A total of 334 cases with CHD and 788 healthy controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing LINE-1 repeats using bisulfite pyrosequencing.

Results

In an initial analysis restricted to control subjects, LINE-1 level reduced significantly with aging, elevated total cholesterol, and diagnosis of diabetes. In the case-control analysis, reduced LINE-1 methylation was associated with increased risk of CHD; analysis by quartile revealed odds ratios (95%CI) of 0.9 (0.6-1.4), 1.9 (1.3-2.9) and 2.3 (1.6-3.5) for the third, second and first (lowest) quartile (P_trend < 0.001), respectively, compared to the fourth (highest) quartile. Lower (<median) LINE-1 methylation was associated with a 2.2-fold (95%CI = 1.7-3.0) increased risk of CHD. The lower LINE-1-related CHD risk estimates tended to be stronger among subjects with the highest tertile of homocysteine (P_interaction = 0.042) and those with diagnosis of hypertension (P_interaction = 0.012).

Conclusion

LINE-1 hypomethylation is associated with the risk of CHD in Chinese population. Potential CHD risk factors such as older age, elevated total cholesterol, and diagnosis of diabetes may have impact on global DNA methylation, whereby exerting their effect on CHD risk.     

Honeybees and cell lines as models of DNA methylation and aging in response to diet

DNA methylation patterns change as individuals grow older, and DNA methylation appears susceptible to modification by the diet. Thus DNA methylation may be a mechanism through which diet can affect aging and longevity. We propose that effects on DNA methylation also contribute to the extension in lifespan observed in response to dietary restriction. Relationships between diet-induced changes in DNA methylation and parallel effects on aging and/or lifespan could, of course, be purely associative. Proof of these ideas requires experimental model systems in which it is possible to manipulate genome methylation status and to measure effects on aging and/or lifespan. Commonly-used short-lived and genetically-malleable metazoan species, such as Caenorhabditis elegans and Drosophila, are not suitable for such studies; the C. elegans genome is not methylated, and DNA methylation in Drosophila is dissimilar from mammalian DNA methylation, occurring at cytosines at sites other than in CpG sequences. The honeybee provides a potentially unique and tractable model for such studies. Female larval development into the long-lived queen phenotype or short-lived worker is determined purely by diet (royal jelly) through an effect on DNA methylation, and honeybee DNA methylation mirrors that of the mammalian genome. Mammalian cell lines and biochemical approaches offer complementary tools to address specific components of hypotheses relating to effects of diet on aging through DNA methylation in a more targeted manner. Our studies using mammalian cell lines are revealing effects of Sirt1 on DNA methylation, and indicate that Sirt1 and resveratrol affect the expression of different sets of genes.     

Detection of TUNEL-positive cardiomyocytes and c-kit-positive progenitor cells in children with congenital heart disease

The loss of cardiomyocytes by apoptosis and the subsequent replacement by fibrous connective tissues are important features of cardiac remodeling in adult heart disease. In children with CHD, however, the cellular and molecular mechanisms of heart failure have not yet been fully understood because of the anatomical and hemodynamic complexities. To investigate the apoptotic death of cardiomyocytes and mobilization of cardiac progenitor cells in children with congenital heart disease (CHD), terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) assay and immunohistochemistry with antibody against c-kit were performed. The incidence of TUNEL-positive cardiomyocytes in children with CHD (n=17) was higher (0.39+/-0.21%) than that in the child controls (0.072+/-0.037%, p<0.001, n=6), however, the incidence was lower than that in adults with heart disease (1.35+/-0.54%, p<0.005, n=7). Significant cardiomyocyte hypertrophy or fibrosis was not observed in children with CHD. The CHD patients hemodynamically demonstrating a volume overload showed more TUNEL-positive cardiomyocytes (0.58+/-0.17%, n=4) than those with severe cyanosis (0.20+/-0.12%, p<0.05, n=4). C-kit-positive cells were more abundantly detected in CHD in comparison to the child control (p<0.01) and the adults with heart disease (p<0.005). The incidence of c-kit-positive cells correlated with that of TUNEL-positive cardiomyocytes (r=0.513). In contrast to adult patients with heart disease where cardiomyocyte apoptosis and the subsequent replacement by fibrous connective tissue are characteristic features of remodeling process, stress in children with CHD was found to induce less cardiomyocyte apoptosis and fibrosis. This study also provides a possible relationship between cardiomyocyte apoptosis and mobilization of c-kit-positive cells in children with CHD.     

Sex,plasma lipoproteins,and atherosclerosis: Prevailing assumptions and outstanding questions

We review the hypothesis that the incidence of coronary heart disease (CHD) is higher in men than in women due to differences in plasma lipoprotein risk factors between the sexes. Men and women appear to be equally susceptible to the effects of lipoprotein risk factors for CHD, and the difference between the sexes in lipoprotein risk factors for CHD appears to be consistent with their being, at least in part, responsible for the sex difference in CHD. This is apparent both when men and women of equal age are compared, and when age-related variations in the sex differences in plasma lipoproteins and CHD are considered. Differences between the sexes in lipoprotein concentrations are still present when sex differences in adiposity, cigarette smoking, physical activity, and diet are taken into account. Evidence relating these sex differences in CHD and lipoproteins to the effects of sex hormones is critically examined. It is commonly accepted that androgens induce changes in lipoprotein concentrations that would predispose towards CHD, whereas estrogens are held to have opposite effects. However, much of the evidence for this comes from studies of changes associated with administration of synthetic gonadal steroids or with changes in gonadal function. Studies of differences in lipoprotein metabolism in normal men and women are extremely limited. In males high-density lipoprotein (HDL) cholesterol levels fall at puberty, correlating with the rise in plasma testosterone concentrations. In females, HDL levels do not change at puberty, despite the rise in estrogen concentrations. Evidence for lipoprotein changes during the menopause, when estrogen levels decline, is equivocal. Similarly, the evidence for an increase in CHD incidence at the menopause is inconclusive. National mortality data indicate that the decreasing sex difference in CHD after 50 years of age is due to a declining rate of increase in men rather than to an acceleration in CHD incidence in women. In men the age-related increase in low-density lipoprotein (LDL) concentrations diminishes beyond 50 years of age, whereas in women the rate of increase remains unchanged. Studies of the effects of gonadectomy are of doubtful relevance in assessing the roles of sex hormones in CHD, and have not been performed with sufficient rigor to provide definitive conclusions. The effects of exogenously administered androgens and estrogens on lipoprotein concentrations have dominated the evaluation of the hypothesis that differences in sex hormones underlie the sex difference in lipoprotein concentrations and hence CHD incidence. However, these studies have been confounded by the variety and nature of gonadal steroids employed, with native (nonsynthetic) hormones being poorly represented. The lack of thorough prospective studies of risk factors for CHD in women, comparative studies of lipoprotein metabolism in healthy men and women, and prospective studies relating endogenous sex hormone levels, plasma lipoprotein concentrations, and development of CHD all remain serious omissions in our understanding of the pathogenesis of the major cause of death in Western society.