DNA Methylation and Epigenotypes

The science of epigenetics is the study of all those mechanisms that control the unfolding of the genetic program for development and determine the phenotypes of differentiated cells. The pattern of gene expression in each of these cells is called the epigenotype. The best known and most thoroughly studied epigenetic mechanism is DNA methylation, which provides a basis both for the switching of gene activities, and the maintenance of stable phenotypes. The human epigenome project is the determination of the pattern of DNA methylation in multiple cell types. Some methylation sites, such as those in repeated genetic elements, are likely to be the same in all cell types, but genes with specialized functions will have distinct patterns of DNA methylation. Another project for the future is the study of the reprogramming of the genome in gametogenesis and early development. Much is already known about the de novo methylation of tumor suppressor genes in cancer cells, but the significance of epigenetic defects during ageing and in some familial diseases remains to be determined.     

Current progress in epigenetic research for hepatocarcinomagenesis

Hepatocellular carcinoma is the main type of primary liver cancer, and also one of the most malignant tumors. At present, the pathogenesis mechanisms of liver cancer are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic aberrance. In the past, people generally thought that genetic mutation is a key event of tumor pathogenesis, and somatic mutation of tumor suppressor genes is in particular closely associated with oncogenesis. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in the underlying DNA sequence. Specific epigenetic processes include DNA methylation, genome imprinting, chromotin remodeling, histone modification and microRNA regulations. This paper reviews recent epigenetics research progress in the hepatocellular carcinoma study, and tries to depict the relationships between hepatocellular carcinomagenesis and DNA methylation as well as microRNA regulation. Supported by National Basic Research Program of China (Grant No. 2006CD910402) and Science and Technology Commission of Shanghai Municipality (Grant No. 05DZ22201 and 08JC1416400).     

Epigenetics in Alzheimer’s Disease: Perspective of DNA Methylation

Research over the years has shown that causes of Alzheimer’s disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer’s disease (AD), late-onset Alzheimer’s disease (LOAD), familial Alzheimer’s disease (FAD), and autosomal dominant Alzheimer’s disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.     

昆虫滞育表观遗传调控的研究进展

滞育是昆虫躲避不良环境的一种策略,对延续昆虫种群具有重要意义.特别是昆虫的兼性滞育,能够受环境的周期性季节变化影响,表观遗传可能在其中扮演重要角色.表观遗传是不依赖DNA序列改变所产生的可遗传变异,包括DNA、RNA、蛋白质和染色质水平上的各种表观遗传调控过程,可能参与生物的发育可塑性.昆虫滞育表观遗传调控主要包括两个...     

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。     

黑色素瘤发生发展中的表观遗传学调控

人恶性黑色素瘤(malignant melanoma)是近年来高发病率和高死亡率的肿瘤之一.目前尚缺乏有效的治疗方法.而表观遗传如DNA甲基化(DNA methylation)、组蛋白修饰(histonemodification)、染色质重塑(chromatin remodeling)及RNA干扰(RNA interference,RNAi)等改变在人黑色素瘤的发生、发展和转移中有重要作用.阐明黑色素瘤发生发展的表观遗传学机制已引起了学者的普遍关注.本文综述了人类黑色素瘤发生发展中所特异的表观遗传改变:CpG岛的异常甲基化修饰、组蛋白甲基化和乙酰化修饰、染色质重塑以及microRNA在黑色素瘤发生和转移中的作用,并对应用表观遗传修饰治疗人类黑色素瘤进行了探讨.     

DNA损伤修复过程表观遗传学改变

多种化学、物理及生物因素可诱发细胞DNA损伤,损伤后DNA损伤位点被相关损伤感受器识别,激活相应的修复通路进行DNA修复。越来越多的证据表明DNA甲基化状态、蛋白翻译后修饰、染色质重塑、miRNA等修饰方式参与了DNA的损伤修复。文章通过不同损伤修复通路中这些修饰的特点,阐述表观遗传学改变在DNA损伤修复发展过程中的作用机制。     

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。     

Do not be scared of the genome's 5th base—Explaining phenotypic variability and evolutionary dynamics through DNA methylation analysis

Epigenetic processes have taken center stage for the investigation of many biological processes, and epigenetic modifications have shown to influence phenotype, morphology and behavioural traits such as stress resistance by affecting gene regulation and expression without altering the underlying genomic sequence. The multiple molecular layers of epigenetics synergistically construct the cell type-specific gene regulatory networks, characterized by a high degree of plasticity and redundancy to create cell-type-specific morphology and function. DNA methylation occurring on the 5′ carbon of cytosines in different genomic sequence contexts is the most studied epigenetic modification. DNA methylation has been shown to provide a molecular record of the exposure to a large variety of environmental factors, which might be persistent through the entire lifetime of an organism and even be passed onto the offspring. Animals might display altered phenotypes mediated by epigenetic modifications depending on the developmental stage or the environmental conditions as well as during evolution. Therefore, the analysis of DNA methylation patterns might allow deciphering previous exposures, explaining ecologically relevant phenotypic diversity and predicting evolutionary trajectories enabling accelerated adaption to changing environmental conditions. Despite the explanatory potential of DNA methylation integrating genetic and environmental factors to shape phenotypic variation and contribute significantly to evolutionary dynamics, studies of DNA methylation are still scarce in the field of ecology. This might be at least partly due to the complexity of DNA methylation analysis and the interpretation of the acquired data. In the current issue of Molecular Ecology Resources, Laine and colleagues (Molecular Ecology Resources, 2022) provide a detailed summary of guidelines and valuable recommendations for researchers in the field of ecology to avoid common pitfalls and perform interpretable genome-wide DNA methylation analyses.     

植物DNA甲基化及其研究策略

DNA甲基化是表观遗传学研究的热点问题之一,植物DNA甲基化的研究对植物研究领域的发展有着举足轻重的作用。本文阐述了植物DNA甲基化的相关机制,其中包括RdDM（RNA—dependent DNA methylation）、DNA甲基化与组蛋白修饰以及DNA去甲基化等近几年研究的热点问题：讨论了DNA甲基化在植物发育中的功能（包括基因组防御和调控基因表达）、DNA甲基化与转基因沉默的关系以及其在表观遗传学中的地位。最后就目前国内外研究植物DNA甲基化所采取的常用策略,即高效液相色谱法、亚硫酸盐测序法、甲基化敏感的限制性内切酶结合Southern杂交分析法和MSAP（methylation—sensitive amplified polymorphism）法进行了详尽的介绍和讨论。     

Retrospective and perspective of plant epigenetics in China

Epigenetics refers to the study of heritable changes in gene function that do not involve changes in the DNA sequence. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors or be part of normal developmental program. In eukaryotes, DNA wraps on a histone octamer (two copies of H2A, H2B, H3 and H4) to form nucleosome, the fundamental unit of chromatin. The structure of chromatin is subjected to a dynamic regulation through multiple epigenetic mechanisms, including DNA methylation, histone posttranslational modifications (PTMs), chromatin remodeling and noncoding RNAs. As conserved regulatory mechanisms in gene expression, epigenetic mechanisms participate in almost all the important biological processes ranging from basal development to environmental response. Importantly, all of the major epigenetic mechanisms in mammalians also occur in plants. Plant studies have provided numerous important contributions to the epigenetic research. For example, gene imprinting, a mechanism of parental allele-specific gene expression, was firstly observed in maize; evidence of paramutation, an epigenetic phenomenon that one allele acts in a single locus to induce a heritable change in the other allele, was firstly reported in maize and tomato. Moreover, some unique epigenetic mechanisms have been evolved in plants. For example, the 24-nt siRNA-involved RNA-directed DNA methylation (RdDM) pathway is plant-specific because of the involvements of two plant-specific DNA-dependent RNA polymerases, Pol IV and Pol V. A thorough study of epigenetic mechanisms is of great significance to improve crop agronomic traits and environmental adaptability. In this review, we make a brief summary of important progress achieved in plant epigenetics field in China over the past several decades and give a brief outlook on future research prospects. We focus our review on DNA methylation and histone PTMs, the two most important aspects of epigenetic mechanisms.     

Epigenetics Alterations in Preneoplastic and Neoplastic Lesions of the Cervix

ABSTRACT: Cervical cancer (CC) is one of the most malignant tumors and the second or third most common type of cancer in women worldwide. The association between human papillomavirus (HPV) and CC is widely known and accepted (99.7% of cases). At present, the pathogenesis mechanisms of CC are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic alterations. In the past, it was generally thought that genetic mutation was a key event of tumor pathogenesis, especially somatic mutation of tumor suppressor genes. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in DNA sequence. Specific epigenetic processes include DNA methylation, chromotin remodeling, histone modification, and microRNA regulations. These alterations, in combination or individually, make it possible to establish the methylation profiles, histone modification maps, and expression profiles characteristic of this pathology, which become useful tools for screening, early detection, or prognostic markers in cervical cancer. This paper reviews recent epigenetics research progress in the CC study, and tries to depict the relationships between CC and DNA methylation, histone modification, as well as microRNA regulations.     

Novel epigenetic therapeutic strategies and targets in cancer

The critical role of dysregulated epigenetic pathways in cancer genesis, development, and therapy has typically been established as a result of scientific and technical innovations in next generation sequencing. RNA interference, histone modification, DNA methylation and chromatin remodelling are epigenetic processes that control gene expression without causing mutations in the DNA. Although epigenetic abnormalities are thought to be a symptom of cell tumorigenesis and malignant events that impact tumor growth and drug resistance, physicians believe that related processes might be a key therapeutic target for cancer treatment and prevention due to the reversible nature of these processes. A plethora of novel strategies for addressing epigenetics in cancer therapy for immuno-oncological complications are currently available - ranging from basic treatment to epigenetic editing. – and they will be the subject of this comprehensive review. In this review, we cover most of the advancements made in the field of targeting epigenetics with special emphasis on microbiology, plasma science, biophysics, pharmacology, molecular biology, phytochemistry, and nanoscience.     

Hot topics in epigenetic mechanisms of aging: 2011

Aging is a complex process that results in compromised biological functions of the organism and increased susceptibility to disease and death. Although the molecular basis of aging is currently being investigated in many experimental contexts, there is no consensus theory to fully explain the aging process. Epigenetic factors, including DNA methylation, histone modifications, and microRNA expression, may play central roles in controlling changes in gene expression and genomic instability during aging. In this Hot Topic review, we first examine the mechanisms by which these epigenetic factors contribute to aging in diverse eukaryotic species including experimental models of yeasts, worms, and mammals. In a second section, we will emphasize in the mammalian epigenetic alterations and how they may affect human longevity by altering stem cell function and/or somatic cell decline. The field of aging epigenetics is ripe with potential, but is still in its infancy, as new layers of complexity are emerging in the epigenetic network. As an example, we are only beginning to understand the relevance of non-coding genome to organism aging or the existence of an epigenetic memory with transgenerational inheritance. Addressing these topics will be fundamental for exploiting epigenetics phenomena as markers of aging-related diseases or as therapeutic targets.     

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.     

A truly ecological epigenetics study

Until a few years ago, epigenetics was a field of research that had nothing to do with ecology and that virtually no ecologist had ever heard of. This is now changing, as more and more ecologists learn about epigenetic processes and their potential ecological and evolutionary relevance, and a new research field of ecological epigenetics is beginning to take shape. One question that is particularly intriguing ecologists is to what extent epigenetic variation is an additional, and hitherto overlooked, source of natural variation in ecologically important traits. In this issue of Molecular Ecology, Herrera & Bazaga (2011) provide one of the first attempts to truly address this question in an ecological setting. They study variation of DNA methylation in a wild population of the rare, long-lived violet Viola cazorlensis, and they use these data to explore interrelations between environmental, genetic and epigenetic variation, and in particular the extent to which these factors are related to long-term differences in herbivore damage among plants. They find substantial epigenetic variation among plant individuals. Interestingly, this epigenetic variation is significantly correlated with long-term differences in herbivory, but only weakly with herbivory-related DNA sequence variation, which suggests that besides habitat, substrate and genetic variation, epigenetic variation may be an additional, and at least partly independent, factor influencing plant–herbivore interactions in the field. Although the study by Herrera & Bazaga (2011) raises at least as many new questions as it answers, it is a pioneering example of how epigenetics can be incorporated into ecological field studies, and it illustrates the value and potential novel insights to be gained from such efforts.