DNA methylation impacts on learning and memory in aging

Learning and memory are two of the fundamental cognitive functions that confer us the ability to accumulate knowledge from our experiences. Although we use these two mental skills continuously, understanding the molecular basis of learning and memory is very challenging. Methylation modification of DNA is an epigenetic mechanism that plays important roles in regulating gene expression, which is one of the key processes underlying the functions of cells including neurons. Interestingly, a genome-wide decline in DNA methylation occurs in the brain during normal aging, which coincides with a functional decline in learning and memory with age. It has been speculated that DNA methylation in neurons might be involved in memory coding. However, direct evidence supporting the role of DNA methylation in memory formation is still under investigation. This particular function of DNA methylation has not drawn wide attention despite several important studies that have provided supportive evidence for the epigenetic control of memory formation. To facilitate further exploration of the epigenetic basis of memory function, we will review existing studies on DNA methylation that are related to the development and function of the nervous system. We will focus on studies illustrating how DNA methylation regulates neural activities and memory formation via the control of gene expression in neurons, and relate these studies to various age-related neurological disorders that affect cognitive functions.     

DNA methylation and apoptosis

DNA methylation is an epigenetic phenomenon known to play an increasingly important role in the etiology of cancer. Changes in DNA methylation patterns particularly in the promoter region of genes either in the form of hypomethylation or hypermethylation can have profound effects on gene expression. Hypermethylation in the promoter region of genes is involved in down regulation of the gene expression. Studies from various cancers have revealed that DNA methylation affects genes involved in different cellular pathways including apoptosis. Apoptosis or programmed cell death plays a vital role in the maintenance of cellular homeostasis, i.e. a balance between cell proliferation and cell death. Cancer cells are known to harbor defects in apoptotic pathway and disruption of apoptosis is considered as an important factor aiding its evolution. Evidence from literature indicates that DNA methylation mediated down regulation of genes involved in apoptosis could be a significant mechanism through which tumor cells avoid apoptosis.     

DNA methylation and autoimmune disease

DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well.     

DNA methylation, imprinting and cancer

It is well known that a variety of genetic changes influence the development and progression of cancer. These changes may result from inherited or spontaneous mutations that are not corrected by repair mechanisms prior to DNA replication. It is increasingly clear that so called epigenetic effects that do not affect the primary sequence of the genome also play an important role in tumorigenesis. This was supported initially by observations that cancer genomes undergo changes in their methylation state and that control of parental allele-specific methylation and expression of imprinted loci is lost in several cancers. Many loci acquiring aberrant methylation in cancers have since been identified and shown to be silenced by DNA methylation. In many cases, this mechanism of silencing inactivates tumour suppressors as effectively as frank mutation and is one of the cancer-predisposing hits described in Knudson's two hit hypothesis. In contrast to mutations which are essentially irreversible, methylation changes are reversible, raising the possibility of developing therapeutics based on restoring the normal methylation state to cancer-associated genes. Development of such therapeutics will require identifying loci undergoing methylation changes in cancer, understanding how their methylation influences tumorigenesis and identifying the mechanisms regulating the methylation state of the genome. The purpose of this review is to summarise what is known about these issues.     

DNA methylation in cancer and ageing

Epigenetic gene silencing through DNA methylation is now clearly thought to be one of the important steps in the mechanism underlying tumourigenesis. The methylation of several genes increases with age in normal tissues such as the colon. Methylation related to cancer and ageing may lead to new biomarkers and therapeutic concepts for cancer.     

Prediction of methylation CpGs and their methylation degrees in human DNA sequences

DNA methylation plays a key role in the regulation of gene expression. The most common type of DNA modification consists of the methylation of cytosine in the CpG dinucleotide. The detections of DNA methylation have been determined mostly by experimental methods, which were time-consuming and expensive, difficult to meet the requirements of modern large-scale sequencing technology. Accordingly, it is necessary to develop automatic, reliable prediction methods for DNA methylation. In this study, the trinucleotide composition, a 64-dimensional feature vector of the occurrence frequency of 64 trinucleotides in the DNA sequence, was utilized to model SVM for the prediction of CpG methylation degrees in humans. The model was evaluated by jackknife validation and the correlation coefficient (R) and root-mean-square error (RMSE) were 0.8223 and 0.2042, respectively. The proposed method was also used to predict methylation sites, the model was evaluated by jackknife validation and the Matthews correlation coefficient (MCC) and accuracy (ACC) were 0.6263 and 0.8133, respectively. The good results indicated that the proposed method was a useful tool for the investigation of DNA methylation prediction research.     

Chloroplast DNA methylation and inheritance in Chlamydomonas

When Chlamydomonas reinhardtii cells mate, a zygotic maturation program is activated, part of which leads to destruction of chloroplast DNA (cpDNA) from the mating type minus (mt-) parent, and, therefore, to uniparental inheritance of mating type plus (mt+) cpDNA. A long-standing model that explains the selective destruction of mt(-) cpDNA in zygotes invokes a methylation-restriction system. We tested this model by using the potent methylation inhibitor 5-aza-2'-deoxycytidine (5adc) to hypomethylate parental cpDNA and found that the pattern of cpDNA inheritance is altered by 5adc in a manner that is consistent with the model. Surprisingly, however, hypomethylated mt+ cpDNA is not destroyed in zygotes as the methylation-restriction model predicts it should be. Destruction of mt- cpDNA is also unaffected when the parental mt+ cpDNA is hypomethylated. Instead, loss of methylation affects the relative rates of replication of residual mt- cpDNA and mt+ cpDNA in germinating zygotes. The mode of action for 5adc on cpDNA replication in germinating zygotes may be via hypomethylation of mt+ cpDNA, but is also consistent with its action as a DNA-damaging agent. Interestingly, 5adc causes reduced cpDNA replication only in germinating zygotes, not in vegetatively grown cells, indicating that cpDNA replication is qualitatively different in these two stages of the life cycle. Our results demonstrate that methylation is not necessary for protection of the mt+ cpDNA in early zygotes and uncover a novel stage of the Chlamydomonas life cycle when replication of cpDNA is highly susceptible to perturbation. Our data support a model in which differential cpDNA replication in germinating zygotes is used as a mechanism to selectively amplify intact and properly methylated cpDNA molecules.     

DNA甲基化及其调控与肿瘤

表观遗传学是调控肿瘤发生的重要机制之一,其最为常见的方式是甲基化。DNA甲基化通过调节基因的表达影响胚胎发育及肿瘤发生。癌基因启动子区的低甲基化导致其转录激活,抑癌基因启动子区的高甲基化导致其转录抑制,这两者是肿瘤形成的重要途径。     

衰老对DNA甲基化的影响

衰老的生化影响非常复杂,伴随着发生蛋白质、脂类和核酸的生物学明显改变,这些改变的一个重要方面就是DNA的甲基化,DNA甲基化是基因表达修饰的一种机制,基因调节元件内或附近序列的甲基化能通过DNA结合蛋白和染色质结构抑制基因的表达,依赖组织和基因伴随衰老发生甲基化的升高和降低,这些改变能产生病理效果包括恶性肿瘤发生,与衰老有关的自身免疫性疾病,以及其它可能的疾病.因此,虽然衰老会影响DNA甲基化,但DNA甲基化改变也会影响衰老.本篇综述概述伴随衰老一些特异基因甲基化状态改变的事实以及DNA甲基化型式改变的机制.因为这个领域仍然在发展中,可以预计这一领域的新知识会快速增长.     

DNA甲基化水平定量分析方法研究进展

DNA甲基化是基因表达的重要调控方式,在人类胚胎发育和肿瘤形成过程中发挥重要作用,已成为科学界关注的前沿和热点之一.基因组DNA甲基化分析方法较多,现代仪器分析的方法如高效液相色谱-串联质谱(high performance liquid chromatography-tandem mass spectrometry,LC-MS/MS)等具有分析速度快、选择性高和灵敏度高等优点,比传统的分析方法具有更广泛的应用前景.本文就基因组DNA甲基化的定量分析方法作一综述.