组蛋白修饰与相关疾病研究

<正>表观遗传学是针对不涉及DNA序列变化而表现为DNA甲基化谱、染色质结构状态和基因表达谱在细胞间传递的遗传现象的一门科学。目前表观遗传学通常被定义为基因表达通过有丝分裂或减数分裂发生了可遗传的改变,而DNA序列不发生改变〔1〕。其机制主要包括DNA甲基化、组蛋白修饰及非编码RNA。目前已知核小体组蛋白蛋白质的共价翻译后修饰在基因调控中发挥着重要作用。常见的组蛋白尾部修饰方式     

表观遗传学与肺癌

表观遗传学是指无DNA序列变化、可遗传的基因表达的改变.表观遗传学的分子机制主要包括DNA甲基化及组蛋白修饰,这些生物大分子的修饰在细胞周期,基因组印记、X染色体的失活中起重要作用.表观遗传学的改变与肿瘤及肺癌的发生、发展密切相关,它在疾病中的重要性越来越受到关注,表观遗传学的改变有可能成为新的诊断、监测及治疗的工具.     

表观遗传修饰与肿瘤

表观遗传学是指基因表达或蛋白表达的改变不涉及DNA序列变化,但又可以通过细胞分裂和增殖而稳定遗传的现象,主要包括基因组印记、DNA甲基化、组蛋白修饰和非编码RNA等。近年来,随着人们对表观遗传学认识的深入,尤其是去甲基化药物阿扎胞苷(azacitidine)及其脱氧衍生物5-氮杂2’-脱氧胞苷(5-Aza-dC)在治疗肿瘤患者的成功临床应用,表观遗传学逐渐成为肿瘤研究热点,本文就DNA甲基化和组蛋白修饰在肿瘤诊断及治疗等方面的研究作简要介绍。     

表观遗传学与肺癌

表观遗传学是指无DNA序列变化、可遗传的基因表达的改变。表观遗传学的分子机制主要、N包括DNA甲基化及组蛋白修饰,这些生物大分子的修饰在细胞周期、基因组印记、x染色体的失活中起重要作用。表观遗传学的改变与肿瘤及肺癌的发生、发展密切相关,它在疾病中的重要性越来越受到关注,表观遗传学的改变有可能成为新的诊断、监测及治疗的工具。     

表观遗传学和肾脏疾病

表观遗传学是研究基因的核苷酸序列不发生改变的情况下发生可遗传修饰的一门学科。表观遗传机制包括DNA甲基化、组蛋白修饰、基因组印记、母体效应、基因沉默和非编码RNA的调控作用等。目前,对于表观遗传学的研究主要集中在DNA甲基化、组蛋白修饰和非编码RNA的调控上,其机制在肾脏疾病的发生和发展中亦起重要作用。     

动脉粥样硬化的表观遗传学研究进展

动脉粥样硬化是环境因素与遗传因素相互作用所致的慢性炎症疾病.表观遗传修饰可能是链接环境因素与遗传因素的桥梁,深入了解表观遗传修饰如DNA甲基化、组蛋白修饰以及微小RNA对动脉粥样硬化形成和发展的影响及其作用机制,将进一步阐明动脉粥样硬化的发病机制.并且由于表观遗传修饰可逆,这可能为动脉粥样硬化的治疗提供新的策略和靶点.     

经典组蛋白去乙酰化酶在中枢神经系统中作用

<正>表观遗传学是指不改变脱氧核糖核酸(DNA)序列而产生的可遗传变化,其在调节基因组功能中发挥关键作用,影响基因表达和(或)转录,从而调控机体的生长、发育及病理过程^[1]。表观遗传学修饰主要包括DNA甲基化、组蛋白修饰和非编码核糖核酸(RNA)等。组蛋白乙酰化核酸修饰是调节DNA功能的重要方式,近年来,研究表明组蛋白乙酰化在神经系统疾病发生发展中起重要作用^[2]。     

组蛋白甲基化修饰在动脉粥样硬化发生发展中的研究进展

随着人们生活方式的改变,动脉粥样硬化的发病率逐年增长。目前,表观遗传学机制已成为动脉粥样硬化发病机制研究的新热点,组蛋白修饰作为一种重要的表观遗传调控机制得到了广泛的关注与研究。其中,组蛋白甲基化修饰是组蛋白修饰的重要形式之一,研究表明其与动脉粥样硬化的发生发展有着密不可分的联系。本文以几个重要的组蛋白甲基化修饰位点在动脉粥样硬化发生发展中的作用作为切入点,对这一领域的研究进展进行综述。     

心房颤动的表观遗传学研究进展

心房颤动(房颤)是一种遗传因素和环境因素共同导致的心律失常, 发病率高, 危害严重, 研究房颤的发生机制具有重大临床意义。表观遗传学是研究基因序列不发生改变的情况下, 基因表达发生可遗传变化的遗传学分支学科。表观遗传学修饰与房颤的发生、发展密切相关, DNA甲基化、组蛋白修饰和非编码RNA调控等机制在基因的转录、翻译、心房电重塑、结构重塑和自主神经功能改变等过程中发挥重要作用, 为房颤表观遗传学研究开拓了房颤发生机制研究的新思路, 可能为房颤治疗提供潜在靶点。     

糖尿病大血管病变的表观遗传学标志物

表观遗传学是指在不改变核苷酸序列的情况下,基因的表达活性发生了可遗传的变化,它包括DNA甲基化、组蛋白修饰、miRNA等.表观遗传学在糖尿病大血管病变的发生、发展过程发挥了重要的作用.近年来研究发现了一些反映糖尿病大血管病变的表观遗传学标志物,包括LINE-1甲基化、Alu甲基化、DDAH2启动子甲基化;Sirt1与SET7等组蛋白修饰相关酶;miRNA-126、miRNA-21、miRNA-125b等.随着表观遗传改变检测手段的改进,表观遗传学标志物有可能成为糖尿病大血管病变新的诊断手段.     

The role of epigenetic alterations in pancreatic cancer

The past several years have witnessed an explosive increase in our knowledge about epigenetic features in human cancers. It has become apparent that pancreatic cancer is an epigenetic disease, as it is a genetic disease, characterized by widespread and profound alterations in DNA methylation. The introduction of genome-wide screening techniques has accelerated the discovery of a growing list of genes with abnormal methylation patterns in pancreatic cancer, and some of these epigenetic events play a role in the neoplastic process. The detection and quantification of DNA methylation alterations in pancreatic juice is likely a promising tool for the diagnosis of pancreatic cancer. The potential reversibility of epigenetic changes in genes involved in tumor progression makes them attractive therapeutic targets, but the efficacy of epigenetic therapies in pancreatic cancer, such as the use of DNA methylation inhibitors, remains undetermined. In this review, we briefly summarize recent research findings in the field of pancreatic cancer epigenetics and discuss their biological and clinical implications.     

Epigenetics and pancreatic cancer:Pathophysiology and novel treatment aspects

An improvement in pancreatic cancer treatment represents an urgent medical goal.Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades.Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations,such as mutations of K-ras,and especially epigenetic dysregulation of tumor-associated genes,such as silencing of the tumor suppressor p16ink4a,are hallmarks of pancreatic cancer.Here,we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation,histone acetylation or miRNA(microRNA)expression,and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition,morphological pattern formation,or cancer stem cell regulation during carcinogenesis from PanIN(pancreatic intraepithelial lesions)to invasive cancer and resistance development.Epigenetic drugs,such as DNA methyltransferases or histone deactylase inhibitors,have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development.Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.     

Helicobacter pylori and epigenetic mechanisms underlying gastric carcinogenesis

Gastric carcinogenesis is a multistep process triggered by Helicobacter pylori and characterized by accumulation of molecular alterations. Two mechanisms are implicated in cancer-related molecular alterations: genetic and epigenetic. The former includes changes in the DNA sequence, the latter occurs without changes of DNA sequence. However, the most important difference between genetic and epigenetic alterations is that epigenetic changes are potentially reversible by eliminating toxic agents. DNA methylation is the major epigenetic phenomenon of eukaryotic genomes and involves the addition of a methyl group to the carbon 5 position of the cytosine ring within the CpG dinucleotide. DNA methylation is needed for the normal development of cells, whereas aberrant methylation of CpG islands confers a selective growth advantage that results in cancerous growth. The stomach is one of the organs frequently showing aberrant methylation of DNA epithelial cells because of its accessibility to exogenous toxic agents such as H. pylori infection. Aberrant methylation of CpG islands occurs early in gastric carcinogenesis, tends to increase as the process advances and is prevalently related to the infection. In conclusion, gastric cancer is mainly an epigenetic disease and H. pylori, acting through inflammatory mediators, may play a key role in the development of such molecular alterations.     

The role of epigenetics in colorectal cancer

Colorectal cancer (CRC) results from a stepwise accumulation of genetic and epigenetic alterations that transform the normal colonic epithelium into cancer. DNA methylation represents one of the most studied epigenetic marks in CRC, and three common epigenotypes have been identified characterized by high, intermediate and low methylation profiles, respectively. Combining DNA methylation data with gene mutations and cytogenetic alterations occurring in CRC is nowadays allowing the characterization of different CRC subtypes, but the crosstalk between DNA methylation and other epigenetic mechanisms, such as histone tail modifications and the deregulated expression of non-coding RNAs is not yet clearly defined. Epigenetic biomarkers are increasingly recognized as promising diagnostic and prognostic tools in CRC, and the potential of therapeutic applications aimed at targeting the epigenome is under investigation.     

Accumulation of aberrant DNA methylation during colorectal cancer development

Despite the recent advances in the therapeutic modalities,colorectal cancer(CRC)remains to be one of the most common causes of cancer-related death.CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas.Among crucial roles of epigenetic alterations,gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms.Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes.Each epigenotype cooperates with specific genetic alterations,suggesting that they represent different molecular carcinogenic pathways.Precursor lesions of CRC,such as conventional and serrated adenomas,already show similar methylation accumulation to CRC,and can therefore be classified into those epigenotypes of CRC.In addition,specific DNA methylation already occurs in the normal colonic mucosa,which might be utilized for prediction of the personal CRC risk.DNA methylation is suggested to occur at an earlier stage than carcinoma formation,and may predict the molecular basis for future development of CRC.Here,we review DNA methylation and CRC classification,and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis,prediction of the prognosis and the response to therapy of CRC.     

DNA甲基化在结直肠癌诊疗中的应用前景

目前认为结直肠癌的发生是在环境因素的作用下通过遗传学和表观遗传学的累积性改变所致。表观遗传学修饰,特别是基因启动子区域的DNA甲基化,被认为是肿瘤中普遍发生的分子改变。因此可通过检测基因的异常甲基化等表观遗传学改变对结直肠癌进行预防、早期诊断、临床治疗及预后评价。本文论述了结直肠癌相关基因甲基化状态的研究进展以及表观遗传学的临床应用,目的在于探讨表观遗传学在结直肠癌早期诊断及治疗中的意义。     

DNA methylation disturbances as novel therapeutic target in lung cancer: preclinical and clinical results

The prognosis of lung cancer is very much limited by the difficulties of diagnosing early stage disease amenable to surgery. Thus, novel diagnostic and therapeutic approaches are urgently needed for this common type of cancer. Recently, epigenetic alterations of tumor cells have been defined for a multitude of tissues and genes. Thus, promoter hypermethylation of tumor suppressor genes, and other targets of neoplasia-associated methylation disturbances, have become the most frequent recurrent alteration in solid tumors and hematologic neoplasia. In lung cancer, several sets of genes including the tumor suppressor gene p16, the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), E-cadherin and retinoic acid receptor beta have been shown to be frequently methylated and inactivated. Distinct methylation patterns can provide molecular distinctions between different histologic subtypes of lung cancer. Gene hypermethylation in lung cancer is an early event associated with exposure to tobacco-specific carcinogens. Highly sensitive detection of hypermethylated DNA in sputum and peripheral blood offers a powerful tool for detecting lung cancer at an early stage. Epigenetic alterations in cancer, as opposed to genetic lesions, are potentially reversible. Thus, hypermethylation has been studied as a therapeutic target for agents which revert this epigenotype. The most advanced drugs to inhibit methylation are two azanucleosides, decitabine and its ribonucleoside analogue 5-azacytidine. In vitro, demethylating agents given at low doses reactivate tumor suppressor genes, and in mouse models, the development of lung cancer can be retarded. This effect is more powerful when histone acetylation, as a second epigenetic silencing mechanism, is also inhibited pharmacologically (HDAC inhibitors). Clinical trials of both groups of agents have been performed, and novel demethylating agents which are not incorporated into DNA offer further perspectives for epigenetic therapy of lung cancer and other malignancies.     

Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer

Colon cancer has been viewed as the result of progressive accumulation of genetic and epigenetic abnormalities. However, this view does not fully reflect the molecular heterogeneity of the disease. We have analyzed both genetic (mutations of BRAF, KRAS, and p53 and microsatellite instability) and epigenetic alterations (DNA methylation of 27 CpG island promoter regions) in 97 primary colorectal cancer patients. Two clustering analyses on the basis of either epigenetic profiling or a combination of genetic and epigenetic profiling were performed to identify subclasses with distinct molecular signatures. Unsupervised hierarchical clustering of the DNA methylation data identified three distinct groups of colon cancers named CpG island methylator phenotype (CIMP) 1, CIMP2, and CIMP negative. Genetically, these three groups correspond to very distinct profiles. CIMP1 are characterized by MSI (80%) and BRAF mutations (53%) and rare KRAS and p53 mutations (16% and 11%, respectively). CIMP2 is associated with 92% KRAS mutations and rare MSI, BRAF, or p53 mutations (0, 4, and 31% respectively). CIMP-negative cases have a high rate of p53 mutations (71%) and lower rates of MSI (12%) or mutations of BRAF (2%) or KRAS (33%). Clustering based on both genetic and epigenetic parameters also identifies three distinct (and homogeneous) groups that largely overlap with the previous classification. The three groups are independent of age, gender, or stage, but CIMP1 and 2 are more common in proximal tumors. Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease.     

Interplay among epigenetic alterations and crosstalk between genetic and epigenetic alterations in esophageal squamous cell carcinoma

Epigenetic alterations that do not involve a change in the DNA sequence have been increasingly recognized to be important key events in the regulation of the gene expression and carcinogenesis. Major epigenetic mechanisms include the methylation of cytosine in DNA, changes in the histone and chromatin structure due to covalent posttranslational modification of histone proteins and the RNA-mediated regulation of the gene expression. Esophageal squamous cell carcinoma (ESCC) continues to be associated with a very poor prognosis, indicating that obtaining a clear understanding of the pathogenesis of ESCC is desired for improving clinical outcomes. In this review, we discuss the recent progress in research on epigenetic alterations in ESCC, with respect to the following points: (1) DNA methylation, including global hypomethylation and DNA hypermethylation at CpG islands in the promoters of tumor suppressor genes, (2) histone acetylation/deacetylation and histone methylation with the alteration of histone-modifying enzymes and (3) alterations in the expression of microRNA and the recently emerging long non-coding RNA. We then discuss the interplay among these epigenetic events and the crosstalk between epigenetic and genetic changes in ESCC. It is therefore important to understand the molecular mechanisms underlying the development and progression of ESCC to improve the treatment outcome of this devastating disease, although this information is quite complicated and confusing.     

Diet and epigenetics in colon cancer

Over the past few years, evidence has accumulated indicating that apart from genetic alterations, epigenetic alterations, through e.g. aberrant promoter methylation, play a major role in the initiation and progression of colorectal cancer （CRC）. Even in the hereditary colon cancer syndromes, in which the susceptibility is inherited dominantly, cancer develops only as the result of the progressive accumulation of genetic and epigenetic alterations. Diet can both prevent and induce colon carcinogenesis, for instance, through epigenetic changes, which regulate the homeostasis of the intestinal mucosa. Food-derived compounds are constantly present in the intestine and may shift cellular balance toward harmful outcomes, such as increased susceptibility to mutations. There is strong evidence that a major component of cancer risk may involve epigenetic changes in normal cells that increase the probability of cancer after genetic mutation. The recognition of epigenetic changes as a driving force in colorectal neoplasia would open new areas of research in disease epidemiology, risk assessment, and treatment, especially in mutation carriers who already have an inherited predisposition to cancer.