Mercury‐associated DNA hypomethylation in polar bear brains via the LUminometric Methylation Assay: a sensitive method to study epigenetics in wildlife

In this paper we describe a novel approach that may shed light on the genomic DNA methylation of organisms with non‐resolved genomes. The LUminometric Methylation Assay (LUMA) is permissive for genomic DNA methylation studies of any genome as it relies on the use of methyl‐sensitive and ‐insensitive restriction enzymes followed by polymerase extension via Pyrosequencing technology. Here, LUMA was used to characterize genomic DNA methylation in the lower brain stem region from 47 polar bears subsistence hunted in central East Greenland between 1999 and 2001. In these samples, average genomic DNA methylation was 57.9% ± 6.69 (SD; range was 42.0 to 72.4%). When genomic DNA methylation was related to brain mercury (Hg) exposure levels, an inverse association was seen between these two variables for the entire study population (P for trend = 0.17). After dichotomizing animals by gender and controlling for age, a negative trend was seen amongst male animals (P for trend = 0.07) but no associations were found in female bears. Such sexually dimorphic responses have been found in other toxicological studies. Our results show that genomic DNA methylation can be quantitatively studied in a highly reproducible manner in tissue samples from a wild organism with a non‐resolved genome. As such, LUMA holds great promise as a novel method to explore consequential questions across the ecological sciences that may require an epigenetic understanding.     

DNA甲基转移酶的表达调控及主要生物学功能

DNA甲基化是表观遗传学的重要部分, 同组蛋白修饰相互作用, 通过改变染色质结构, 调控基因表达。在哺乳类细胞或人体细胞中, DNA甲基化与细胞的增殖、衰老、癌变等生命现象有着重大关系。对催化DNA甲基化的DNA甲基转移酶(DNA methyltransferase, Dnmt)的研究可以揭示DNA甲基化对基因表达调控的机制, 从而研究与之相关的重要生命活动。文章以DNA甲基转移酶作为切入点, 探讨DNA甲基转移酶在基因表达调控中发挥的作用及其主要生物学功能。     

The evidence for functional non-CpG methylation in mammalian cells

In mammalian genomes, the methylation of cytosine residues within CpG dinucleotides is crucial to normal development and cell differentiation. However, methylation of cytosines in the contexts of CpA, CpT, and CpC (non-CpG methylation) has been reported for decades, yet remains poorly understood. In recent years, whole genome bisulphite sequencing (WGBS) has confirmed significant levels of non-CpG methylation in specific tissues and cell types. Non-CpG methylation has several properties that distinguish it from CpG methylation. Here we review the literature describing non-CpG methylation in mammalian cells, describe the important characteristics that distinguish it from CpG methylation, and discuss its functional importance.     

Liquid biopsies: DNA methylation analyses in circulating cell-free DNA

Analysis of patient's materials like cells or nucleic acids obtained in a minimally invasive or noninvasive manner through the sampling of blood or other body fluids serves as liquid biopsies, which has huge potential for numerous diagnostic applications. Circulating cell-free DNA (cfDNA) is explored as a prognostic or predictive marker of liquid biopsies with the improvements in genomic and molecular methods. DNA methylation is an important epigenetic marker known to affect gene expression. cfDNA methylation detection is a very promising approach as abnormal distribution of DNA methylation is one of the hallmarks of many cancers and methylation changes occur early during carcinogenesis. This review summarizes the various investigational applications of cfDNA methylation and its oxidized derivatives as biomarkers for cancer diagnosis, prenatal diagnosis and organ transplantation monitoring. The review also provides a brief overview of the technologies for cfDNA methylation analysis based on next generation sequencing.     

植物DNA甲基化及其表观遗传作用

表观遗传学(epigenetics)是研究没有DNA序列变化的、可遗传的基因表达的改变。目前研究表明,表观遗传学在植物生长发育过程中起着极其重要的作用,主要通过包括DNA甲基化、RNA干涉、基因组印记、转基因沉默等多个方面来调控植物的生长发育。其中,DNA甲基化是表观遗传学的最重要研究内容之一,是调节基因组功能的重要手段。现对植物DNA甲基化的特征、维持机制、调控机制、表观遗传作用及其研究方法进行简要论述。     

Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas

Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. While cytogenetic abnormalities have been well characterized in this disease, aberrant epigenetic events such as DNA hypermethylation have not been described in genome-wide studies. We have analyzed the methylation status of 25,500 promoters in normal skeletal muscle, and in cell lines and tumor samples of embryonal and alveolar rhabdomyosarcoma from pediatric patients. We identified over 1,900 CpG islands that are hypermethylated in rhabdomyosarcomas relative to skeletal muscle. Genes involved in tissue development, differentiation, and oncogenesis such as DNAJA4, HES5, IRX1, BMP8A, GATA4, GATA6, ALX3, and P4HTM were hypermethylated in both RMS cell lines and primary samples, implicating aberrant DNA methylation in the pathogenesis of rhabdomyosarcoma. Furthermore, cluster analysis revealed embryonal and alveolar subtypes had distinct DNA methylation patterns, with the alveolar subtype being enriched in DNA hypermethylation of polycomb target genes. These results suggest that DNA methylation signatures may aid in the diagnosis and risk stratification of pediatric rhabdomyosarcoma and help identify new targets for therapy.     

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.     

动物DNA甲基化研究现状

DNA甲基化作为重要的表观遗传修饰,参与了动物细胞分化、胚胎发育、基因组印记和性染色体失活等多种生物学过程。随着DNA甲基化测序技术的逐渐成熟,使用该技术解决更多动物学问题成为可能。本文综述了DNA甲基化的遗传学特征,重点介绍了DNA甲基化在动物中的研究及应用现状。     

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。     

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.     

BSP技术在萝卜-芥蓝异源四倍体及其亲本BZIP17同源基因甲基化检测中的应用

为探讨异源多倍体基因组中直系同源基因的表达调控机制,对重亚硫酸盐测序PCR(BSP)技术进行了改进优化。结果表明,改进的BSP技术检测到萝卜-芥蓝四倍体及其亲本BZIP17同源基因启动子的甲基化水平为3.8%~18.8%,采用实时荧光定量PCR检测BZIP17基因的相对表达量,且BZIP17同源基因的表达调控与启动子甲基化等作用相关。因此,改进的BSP技术可应用到更多同源基因的甲基化检测中,以分析异源多倍体中同源基因的分子进化方式。