DNA甲基化的生物信息学研究进展

作为重要的表观遗传学现象之一,DNA甲基化对基因的表达发挥重要的调控功能．随着高通量检测技术的不断发展,对DNA甲基化的生物信息学研究也成为DNA甲基化研究中的一个非常活跃的热点．对生物信息学在DNA甲基化状态的预测、CpG岛不易被甲基化的机制研究、探索DNA甲基化同其他表观遗传学现象之间的关系以及DNA异常甲基化同癌症的发生和发展之间的关系等方面的研究进展进行综述．     

同卵双胞胎在复杂性状DNA甲基化调控机制研究中的应用

同卵双胞胎来源于同一个受精卵,DNA序列基本一致,但在某些重要表型上如复杂疾病,并不完全一样。利用表型不一致的同卵双胞胎进行研究,能在遗传背景、母体效应、年龄性别效应等一致的基础上,深入研究分析复杂性状的表观调控机制。而DNA甲基化是最为稳定的一类表观遗传修饰。在人类中,利用同卵双胞胎对印记异常疾病、精神类疾病、自身免疫病及癌症等疾病的DNA甲基化调控研究已经揭示了多个致病基因,为研究疾病的表观调控以及表观遗传学药物的应用打下了基础。本文着重对同卵双胞胎DNA甲基化状态、DNA甲基化遗传力计算以及复杂性状DNA甲基化调控的研究应用及其进展展开综述,以期为复杂性状表观调控机制研究提供借鉴和参考。     

精子DNA甲基化异常与男性不育

DNA甲基化／去甲基化是表观遗传学最重要的内容并可以控制基因的表达和印迹,越来越多的研究显示DNA甲基化异常与不育男性精子发生异常、特定肿瘤的发生、神经系统疾病、Rett综合征等有关。文章通过总结近来的相关研究资料来阐述精子发生过程中的DNA甲基化状态的改变,探讨精子DNA的甲基化异常与男性不育之间的联系,旨在为男性不育的治疗提供新的临床思路。     

前列腺癌的DNA甲基化及其临床应用

目前认为恶性肿瘤的形成是遗传和表观遗传机制共同作用的结果。表观遗传机制包括DNA甲基化、组蛋白修饰和miRNA。DNA异常甲基化(高甲基化和低甲基化)是前列腺癌最具特征的表观遗传改变, 它能够导致基因组不稳定, 调控基因的异常表达, 在前列腺癌的形成和发展中起到重要作用。同时, DNA甲基化作为前列腺癌表观遗传研究的一个热点, 为临床前列腺癌的早期诊断、预后评估及药物治疗提供新的方法和途径。文章根据前列腺癌的DNA高甲基化和低甲基化的最新研究成果阐述了前列腺癌形成的表观遗传学机制, 并且讨论了它们在前列腺癌临床转化方面的最新研究进展。     

DNA甲基化与食管腺癌关系研究进展

癌症本质上是一种多种因素导致的基因疾病。作为肿瘤形成假说中的重要补充内容,表观遗传学已经成为新的研究中心。DNA甲基化是人类基因组发生最为常见的一种表观遗传学事件,因而研究甲基化与肿瘤的关系成为当前分子生物学的热点之一。这篇综述是关于DNA甲基化与食管腺癌的研究进展,包括DNA高甲基化异常与食管腺癌的发生,以及针对甲基化的检测手段,诊断,治疗以及预后。     

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。     

DNA甲基化分析方法

DNA甲基化是表观遗传学的重要研究内容之一.甲基化分析的方法多且研究难度大,各种方法都有其一定的优势和不足.本文综述了基因组DNA甲基化和特定DNA片段甲基化状态分析方法新进展,为研究者提供参考.     

DNA甲基化及其与胃癌相关研究进展

DNA甲基化是表观遗传学中的研究热点,与肿瘤的发生、发展、诊断、治疗、预后等相关。胃癌的发生、发展与DNA甲基化状态改变关系密切,研究胃癌相关基因DNA甲基化状态的改变有助于胃癌的早期发现、诊断、治疗及预后。因此,研究胃癌相关基因的甲基化状态具有一定的临床价值。     

DNA 甲基化及其与胃癌相关研究进展

DNA甲基化是表观遗传学中的研究热点,与肿瘤的发生、发展、诊断、治疗、预后等相关。胃癌的发生、发展与DNA甲基化状态改变关系密切,研究胃癌相关基因DNA甲基化状态的改变有助于胃癌的早期发现、诊断、治疗及预后。因此,研究胃癌相关基因的甲基化状态具有一定的临床价值。     

siRNA诱导的DNA甲基化与肿瘤的发生

siRNA诱导的基因沉默最早只被认为是发生在细胞质内的转录后水平的调控过程,随着siRNA指导DNA甲基化现象的发现,已证实siRNA可以通过指导基因组表观修饰引起转录水平基因沉默.DNA甲基化曾被预言是致癌作用的一种表观遗传学机制,肿瘤发生过程中抑瘤基因异常沉默涉及到基因启动子区域DNA的甲基化.分析了这两个过程中内在的关系,探索siRNA对肿瘤细胞中基因异常表达的影响和作用.这将有助于肿瘤生物学和表观遗传学的研究,也会为研发防治肿瘤的新方法和新途径提供新的思路.     

DNA methylation profiling in cancer: From single nucleotides towards the methylome

The genomic DNA methylation pattern (methylome) is a cell epigenetic program that controls the expression of genetic information. The methylation pattern substantially changes in early carcinogenesis. A detailed survey of the methylcytosine distribution in the genome in norm and pathology is of immense importance for a better understanding of the etiology of cancer and its early diagnosis. The techniques available make it possible to simultaneously examine many samples (high-throughput analysis) and to examine large genome loci or even the total methylome (large-scale analysis). The review considers the main trends in the development of new approaches to DNA methylation and describes the techniques most commonly used in the field, their application, and results. Emphasis is placed on the use of various DNA microarrays (oligonucleotide microarrays, BAC arrays, etc.) as a method of choice for epigenetic analysis of tumors. Alternative sequence-based techniques of methylation analysis are discussed. The use of large-scale analysis to identify new epigenetic markers and to develop an epigenetic classification of neoplasms is considered.     

DNA methylation profiling in cancer: from single nucleotides towards methylome

Genomic DNA methylation pattern (methylome) represents epigenetic program of a cell. It controls expression of genetic information. In tumor cells, significant alterations in DNA methylation take place, which can be identified as one of the earliest and most consistent features of tumorigenesis. Detailed survey of methylcytosines' distribution in genome is extremely important for understanding of real tumor etiology and early diagnostics. Progress in the field has been hampered by the unavailability of methods for large-scale determination of methylation patterns. Nowadays, variety of techniques is in development that allow for highly parallel regime of samples analysis (high-throughput analysis) or large loci DNA profiling (large-scale analysis). Aim of the work is to consider the main trends in the field of new methods development. The principles of the most frequently used approaches to DNA methylation studies are reviewed as well as their application and results. Most attention is paid to DNA microarrays as a technology of choice for epigenetic tumor analysis (oligonucleotide microarrays, BAC-arrays etc.). Alternative DNA sequencing based techniques are discussed, which can soon take on the leadership. Results of a large-scale analysis can be used for identification of new epigenetic markers and epigenetic classification of neoplasia.     

The Russian Biological Student Microscopes

Our out-of-school practical exercise was designed to bring upper secondary school students in contact with one of the most exciting and expanding topics in biology today: epigenetics. In school, students only study the basics in genetics and the respective investigation techniques as provided by the syllabus. For a practical exercise in epigenetics, however, they need additional knowledge. Hence, they are introduced to the subject of epigenetics and its molecular mechanisms. Students are asked to examine the different DNA methylation conditions of lambda DNA using both a restriction assay and gel electrophoresis in an out-of-school laboratory. DNA methylation is one of the major epigenetic mechanisms which have significant effects on gene expression; studies on monozygotic twins have shown that it is influenced by the environment. This exercise enables students to correctly identify the different methylation conditions of distributed lambda DNA samples. In doing so, they receive a first introduction to one epigenetic mechanism. The necessity for students to experience science in out-of-school settings has been shown by several scholars. The practical exercise we are proposing in this article was elaborated for such learning opportunities for upper secondary students to gain insight into contemporary science issues.     

DNA甲基化与肿瘤

表观遗传指不涉及DNA序列改变的,可随细胞分裂而遗传的基因组修饰作用;DNA甲基化是其中研究最多的基因表达调节机制。异常DNA甲基化可致肿瘤发生,它亦是肿瘤基因诊断和治疗的靶点。文章介绍DNA甲基化基本概念、作用效果及其可能机制;并讨论异常DNA甲基化与肿瘤的关联,包括肿瘤中DNA异常甲基化原因、异常甲基化致瘤机制及基因甲基化研究在肿瘤诊治中的应用等。     

Tissue dependent variations of DNA methylation and endoreduplication levels during tomato fruit development and ripening

Tomato fruit cells are characterized by a strong increase in nuclear ploidy during fruit development. Average ploidy levels increased to similar levels (above 50C) in two distinct fruit tissues, pericarp and locular tissue. However, ploidy profiles differed significantly between these two tissues suggesting a tissue-specific control of endoreduplication in tomato fruit. To determine possible relationships between endoreduplication and epigenetic mechanisms, the methylation status of genomic DNA from pericarp and locular tissue of tomato fruit was analysed. Pericarp genomic DNA was characterized by an increase of CG and/or CNG methylation at the 5S and 18S rDNA loci and at gyspsy-like retrotransposon sequences during fruit growth. A sharp decrease of the global DNA methylation level together with a reduction of methylation at the rDNA loci was also observed in pericarp during fruit ripening. Inversely, no major variation of DNA methylation either global or locus-specific, was observed in locular tissue. Thus, tissue-specific variations of DNA methylation are unlikely to be triggered by the induction of endoreduplication in fruit tissues, but may reflect tissue-specific ploidy profiles. Expression analysis of eight putative tomato DNA methyltransferases encoding genes showed that one chromomethylase (CMT) and two rearranged methyltransferases (DRMs) are preferentially expressed in the pericarp during fruit growth and could be involved in the locus-specific increase of methylation observed at this developmental phase in the pericarp.     

Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers

In mammalian development, epigenetic modifications, including DNA methylation patterns, play a crucial role in defining cell fate but also represent epigenetic barriers that restrict developmental potential. At two points in the life cycle, DNA methylation marks are reprogrammed on a global scale, concomitant with restoration of developmental potency. DNA methylation patterns are subsequently re-established with the commitment towards a distinct cell fate. This reprogramming of DNA methylation takes place firstly on fertilization in the zygote, and secondly in primordial germ cells (PGCs), which are the direct progenitors of sperm or oocyte. In each reprogramming window, a unique set of mechanisms regulates DNA methylation erasure and re-establishment. Recent advances have uncovered roles for the TET3 hydroxylase and passive demethylation, together with base excision repair (BER) and the elongator complex, in methylation erasure from the zygote. Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood. In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events. Advances in our understanding of such natural epigenetic reprogramming are beginning to aid enhancement of experimental reprogramming in which the role of potential mechanisms can be investigated in vitro. Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine.     

DNA甲基化异常与肿瘤耐药

肿瘤耐药是导致肿瘤化疗失败的主要原因, 其产生机制复杂多样, 是多种因素共同作用的结果。近年来, 表观遗传改变在肿瘤耐药中的作用日益受到关注。DNA甲基化是一种重要的表观遗传修饰, 在调节基因表达和维持基因组稳定性中扮演着重要角色。原发性或获得性耐药的肿瘤细胞大多伴随DNA异常甲基化, 越来越多的证据显示, DNA甲基化异常是肿瘤细胞耐药表型产生的重要机制。文章就DNA甲基化异常与肿瘤细胞耐药的关系及相关作用机制进行了综述。     

Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray

DNA methylation, an important type of epigenetic modification in humans, participates in crucial cellular processes, such as embryonic development, X-inactivation, genomic imprinting and chromosome stability. Several platforms have been developed to study genome-wide DNA methylation. Many investigators in the field have chosen the Illumina Infinium HumanMethylation microarray for its ability to reliably assess DNA methylation following sodium bisulfite conversion. Here, we analyzed methylation profiles of 489 adult males and 357 adult females generated by the Infinium HumanMethylation450 microarray. Among the autosomal CpG sites that displayed significant methylation differences between the two sexes, we observed a significant enrichment of cross-reactive probes co-hybridizing to the sex chromosomes with more than 94% sequence identity. This could lead investigators to mistakenly infer the existence of significant autosomal sex-associated methylation. Using sequence identity cutoffs derived from the sex methylation analysis, we concluded that 6% of the array probes can potentially generate spurious signals because of co-hybridization to alternate genomic sequences highly homologous to the intended targets. Additionally, we discovered probes targeting polymorphic CpGs that overlapped SNPs. The methylation levels detected by these probes are simply the reflection of underlying genetic polymorphisms but could be misinterpreted as true signals. The existence of probes that are cross-reactive or of target polymorphic CpGs in the Illumina HumanMethylation microarrays can confound data obtained from such microarrays. Therefore, investigators should exercise caution when significant biological associations are found using these array platforms. A list of all cross-reactive probes and polymorphic CpGs identified by us are annotated in this paper.