Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome

DNA methylation gradiently changes with age and is likely to be involved in aging-related processes with subsequent phenotype changes and increased susceptibility to certain diseases. The Hutchinson-Gilford Progeria (HGP) and Werner Syndrome (WS) are two premature aging diseases showing features of common natural aging early in life. Mutations in the LMNA and WRN genes were associated to disease onset; however, for a subset of patients the underlying causative mechanisms remain elusive. We aimed to evaluate the role of epigenetic alteration on premature aging diseases by performing comprehensive DNA methylation profiling of HGP and WS patients. We observed profound changes in the DNA methylation landscapes of WRN and LMNA mutant patients, which were narrowed down to a set of aging related genes and processes. Although of low overall variance, non-mutant patients revealed differential DNA methylation at distinct loci. Hence, we propose DNA methylation to have an impact on premature aging diseases.     

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。     

Identification of a small optimal subset of CpG sites as bio-markers from high-throughput DNA methylation profiles

Background  

DNA methylation patterns have been shown to significantly correlate with different tissue types and disease states. High-throughput methylation arrays enable large-scale DNA methylation analysis to identify informative DNA methylation biomarkers. The identification of disease-specific methylation signatures is of fundamental and practical interest for risk assessment, diagnosis, and prognosis of diseases.     

DNA甲基化微阵列

DNA甲基化微阵列是近年发展起来的高通量分析基因组水平DNA甲基化状态和模式的新型技术,已成为肿瘤表观遗传学组研究的重要工具之一。利用DNA甲基化微阵列研究某种疾病状态下异常甲基化的基因有利于进一步明确该疾病的表观遗传学异常机制,发现与之相关的表观遗传学标志物。现有的DNA甲基化微阵列主要包括CpG岛微阵列和甲基化寡聚核苷探针微阵列,根据已有的文献资料,较为详细地阐述了上述技术的原理、特点和适用范围,对于研究者根据自己的研究目的选择适当的DNA甲基化微阵列技术具有一定的指导价值。     

DNA methylation dynamics in plants and mammals: overview of regulation and dysregulation

DNA methylation is a major epigenetic marking mechanism regulating various biological functions in mammals and plant. The crucial role of DNA methylation has been observed in cellular differentiation, embryogenesis, genomic imprinting and X‐chromosome inactivation. Furthermore, DNA methylation takes part in disease susceptibility, responses to environmental stimuli and the biodiversity of natural populations. In plant, different types of environmental stress have demonstrated the ability to alter the archetype of DNA methylation through the genome, change gene expression and confer a mechanism of adaptation. DNA methylation dynamics are regulated by three processes de novo DNA methylation, methylation maintenance and DNA demethylation. These processes have their similarities and differences between mammals and plants. Furthermore, the dysregulation of DNA methylation dynamics represents one of the primary molecular mechanisms of developing diseases in mammals. This review discusses the regulation and dysregulation of DNA methylation in plants and mammals. Copyright © 2016 John Wiley & Sons, Ltd.     

DNA甲基化调控炎症反应干预As斑块稳定性的研究进展

动脉粥样硬化(As)斑块破裂是导致急性心脑血管事件发生的首要原因。既往对斑块破裂的基础研究多集中于细胞和分子水平,从表观遗传学角度阐述的研究较少。DNA甲基化作为表观遗传学修饰的主要方式之一,可在不改变基因核苷酸序列的情况下影响基因的表达。综合目前研究来看,炎症反应在斑块破裂过程中起关键性作用,而DNA甲基化对炎症反应又起重要的调控作用。因此,改变DNA甲基化状态来调控炎症反应干预As斑块稳定性,有望成为防治As等心脑血管疾病的有效途径之一。本文主要围绕与As炎症反应密切相关的几种炎症免疫细胞及炎症因子等方面,对近年来DNA甲基化调控炎症反应干预As斑块稳定性的研究进展作一综述。     

线粒体DNA与DNA甲基化

线粒体是除细胞核之外唯一携带遗传物质的细胞器,其线粒体DNA（mitochondrial DNA,mtDNA）控制着线粒体一些最基本的性质,对细胞功能有着重要影响.DNA甲基化是调节基因表达的重要方式之一.研究表明mtDNA存在CpG位点的低甲基化,并且mtDNA基因的表达受核DNA（nuclear DNA,nDNA）及线粒体自身DNA甲基化的调控,mtDNA和nDNA协同作用参与机体代谢调节和疾病发生发展过程.就近年来mtDNA与DNA甲基化的关系作一综述.     

Methylation of c-myc gene changes in human lymphoproliferative diseases

The degree of methylation at the c-myc proto-oncogene was found to change in human lymphoproliferative diseases, when examined using a methylation-sensitive restriction enzyme. In peripheral blood mononuclear cells (PBMC) c-myc DNA showed hypomethylation in human lymphoproliferative diseases, in comparison to normal subjects matched in age and sex. In cases of chronic lymphocytic leukemia (CLL), the change was amplified in the crisis. When the DNA was examined at the actin gene, no significant change was observed. The results suggest that the change in c-myc proto-oncogene methylation might become an important clue in understanding the relationship between levels of gene expression and methylation in human lymphoproliferative diseases.     

DNA甲基化与microRNA

细胞中DNA甲基化和microRNA（miRNA）相互影响,并共同调控着下游靶基因的表达活性,在细胞生长代谢、免疫、肿瘤和心血管疾病等生理和病理过程中发挥重要作用。首先简要介绍DNA甲基化与miRNA的概况,然后分析了miRNA调控下的DNA甲基化改变,探讨了DNA甲基化影响miRNA的表达活性变化,并归纳了miRNA与DNA甲基化之间的反馈调控关系;最后对DNA甲基化和miRNA的应用前景进行了简单探讨。研究DNA甲基化与miRNA间的网络调控关系,可为表观调控机制在理论和实践中的深入研究和应用提供参考。     

DNA甲基化与脊椎动物胚胎发育

DNA甲基化是指DNA甲基转移酶(DNMT)将DNA序列中的5′胞嘧啶转变为5′甲基胞嘧啶的化学修饰, 可以调控基因的时空特异性表达, 从而影响细胞命运决定和分化等生物学过程。近年来研究发现, DNA甲基化在脊椎动物胚胎早期发育中有重要作用, Dnmt基因的缺失会影响胚胎早期发育和多个器官的形成及分化, 如胚胎早期致死、内脏器官和神经系统终末分化缺陷以及血液发生紊乱等。文章总结了DNA甲基化转移酶在小鼠和斑马鱼发育过程中的动态变化, 并系统阐述了DNA甲基化在胚胎早期发育和器官发生中的作用, 重点揭示DNA 甲基化转移酶与组蛋白甲基化转移酶如何协同调控DNA甲基化从而影响基因转录的分子机理。DNA甲基化作为一种关键的表观遗传学因素, 全面系统地理解其在胚胎发育过程中的作用机制对靶向治疗人类相关疾病有一定的理论指导意义。     

New findings showing how DNA methylation influences diseases

In 1975, Holliday and Pugh as well as Riggs independently hypothesized that DNA methylation in eukaryotes could act as a hereditary regulation mechanism that influences gene expression and cell differentiation. Interest in the study of epigenetic processes has been inspired by their reversibility as well as their potentially preventable or treatable consequences. Recently, we have begun to understand that the features of DNA methylation are not the same for all cells.Major differences have been found between differentiated cells and stem cells.Methylation influences various pathologies, and it is very important to improve the understanding of the pathogenic mechanisms. Epigenetic modifications may take place throughout life and have been related to cancer, brain aging, memory disturbances, changes in synaptic plasticity, and neurodegenerative diseases,such as Parkinson's disease and Huntington's disease. DNA methylation also has a very important role in tumor biology. Many oncogenes are activated by mutations in carcinogenesis. However, many genes with tumor-suppressor functions are "silenced" by the methylation of CpG sites in some of their regions.Moreover, the role of epigenetic alterations has been demonstrated in neurological diseases. In neuronal precursors, many genes associated with development and differentiation are silenced by CpG methylation. In addition,recent studies show that DNA methylation can also influence diseases that do not appear to be related to the environment, such as IgA nephropathy, thus affecting,the expression of some genes involved in the T-cell receptor signaling. In conclusion, DNA methylation provides a whole series of fundamental information for the cell to regulate gene expression, including how and when the genes are read, and it does not depend on the DNA sequence.     

Decreased global DNA methylation in the white blood cells of high fat diet fed vervet monkeys (Chlorocebus aethiops)

Epigenetic mechanisms are associated with the development of many chronic diseases and due to their reversible nature offer a unique window of opportunity to reverse the disease phenotype. This study investigated whether global DNA methylation correlates with dysglycemia in the vervet monkey (Chlorocebus aethiops). Diet-induced changes in DNA methylation were observed where global DNA methylation was twofold lower in monkeys fed a high fat diet (n?=?10) compared to monkeys fed a standard diet (n?=?15). An inverse correlation was observed between DNA methylation, blood glucose concentrations, bodyweight, and age, although the association was not statistically significant. Consumption of a high fat diet is associated with the development of metabolic disease; thus, these results suggest the use of global DNA methylation as a biomarker to assess the risk for metabolic disease. Moreover, this study provides further support for the use of the vervet monkey as a model system to study metabolic diseases such as type 2 diabetes. Integration of altered DNA methylation profiles into predictive models could facilitate risk stratification and enable intervention strategies to inhibit disease progression. Such interventions could include lifestyle modifications, for example, the increased consumption of functional foods with the capacity to modulate DNA methylation, thus potentially reversing the disease phenotype and preventing disease.     

Methylation analysis by DNA immunoprecipitation

DNA methylation regulates gene expression primarily through modification of chromatin structure. Global methylation studies have revealed biologically relevant patterns of DNA methylation in the human genome affecting sequences such as gene promoters, gene bodies, and repetitive elements. Disruption of normal methylation patterns and subsequent gene expression changes have been observed in several diseases especially in human cancers. Immunoprecipitation (IP)‐based methods to evaluate methylation status of DNA have been instrumental in such genome‐wide methylation studies. This review describes techniques commonly used to identify and quantify methylated DNA with emphasis on IP based platforms. In an effort to consolidate the wealth of information and highlight critical aspects of methylated DNA analysis, sample considerations, experimental and bioinformatic approaches for analyzing genome‐wide methylation profiles, and the benefit of integrating DNA methylation data with complementary dimensions of genomic data are discussed. J. Cell. Physiol. 222: 522–531, 2010. © 2009 Wiley‐Liss, Inc.     

Mechanisms of DNA methylation and demethylation in mammals

Cytosine methylation is an epigenetically propagated DNA modification that can modify how the DNA molecule is recognized and expressed. DNA methylation undergoes extensive reprogramming during mammalian embryogenesis and is directly linked to the regulation of pluripotency and cellular identity. Studying its regulation is also important for a better understanding of the many diseases that show epigenetic deregulations, in particular, cancer. In the recent years, a lot of progress has been made to characterize the profiles of DNA methylation at the genome level, which revealed that patterns of DNA methylation are highly dynamic between cell types. Here, we discuss the importance of DNA methylation for genome regulation and the mechanisms that remodel the DNA methylome during mammalian development, in particular the involvement of the rediscovered modified base 5-hydroxymethylcytosine.     

The regulatory function of piRNA/PIWI complex in cancer and other human diseases: The role of DNA methylation

Piwi-interacting RNAs (piRNAs) are a class of short chain noncoding RNAs that are constituted by 26-30 nucleotides (nt) and can couple with PIWI protein family. piRNAs were initially described in germline cells and are believed to be critical regulators of the maintenance of reproductive line. Increasing evidence has extended our perspectives on the biological significance of piRNAs and indicated that they could still affect somatic gene expression through DNA methylation, chromatin modification and transposon silencing, etc. Many studies have revealed that the dysregulation of piRNAs might contribute to diverse diseases through epigenetic changes represented by DNA methylation and chromatin modification. In this review, we summarized piRNA/PIWI protein-mediated DNA methylation regulation mechanisms and methylation changes caused by piRNA/PIWI proteins in different diseases, especially cancers. Since DNA methylation and inhibitory chromatin marks represented by histone H3 lysine 9 (H3K9) methylation frequently cooperate to silence genomic regions, we also included methylation in chromatin modification within this discussion. Furthermore, we discussed the potential clinical applications of piRNAs as a new type promising biomarkers for cancer diagnosis, as well as the significance of piRNA/PIWI protein-associated methylation changes in treatment, providing disparate insights into the potential applications of them.     

MethMarker: user-friendly design and optimization of gene-specific DNA methylation assays

DNA methylation is a key mechanism of epigenetic regulation that is frequently altered in diseases such as cancer. To confirm the biological or clinical relevance of such changes, gene-specific DNA methylation changes need to be validated in multiple samples. We have developed the MethMarker software to help design robust and cost-efficient DNA methylation assays for six widely used methods. Furthermore, MethMarker implements a bioinformatic workflow for transforming disease-specific differentially methylated genomic regions into robust clinical biomarkers.