The value-added genome: building and maintaining genomic cytosine methylation landscapes

Epigenetic marks, such as cytosine methylation and post-translational histone modifications, are important for interpreting and managing eukaryotic genomes. Recent genetic studies in plants have uncovered details on the different interwoven mechanisms that are responsible for specification of genomic cytosine methylation patterns. These mechanisms include targeting cytosine methylation using heterochromatic histone modifications and RNA guides. Genomic cytosine methylation patterns also reflect locus-specific demethylation initiated by specialized DNA glycosylases. While genetics continues to more fully define these mechanisms, genomic studies in Arabidopsis have yielded an unprecedented high-resolution view of how epigenetic marks are layered over a genome.     

Methylation Modifications in Eukaryotic Messenger RNA

RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA （mRNA）, such as NT-methylguanosine （mVG） at the cap, Nr-methyl-2＇-O-methyladenosine （m6Am）, 2＇-O-methylation （Nm） within the cap and the internal positions, and internal N6-methyladenosine （m6A） and 5-methylcytosine （mSC）. Among them, mTG cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export, m6A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. mrA has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein （FRO） and its homolog protein, alkylation repair ho- molog 5 （ALKBH5）. b-TO has a special demethylation mechanism that demethylases m6A to A through two over-oxidative intermediate states： N6-hydroxymethyladenosine （hm6A） and Nr-formyladenosine （frA）. The two newly discovered m6A demethylases, bTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible mrA, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field ＂RNA Epige- netics＂. 5-methylcytosine （5mC） as an epigenetic mark in DNA has been studied widely, but mSC in mRNA is seldom explored. The bisulfide sequencing showed mSC is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future 19erspectives on functional studies.     

Involvement of putative SNF2 chromatin remodeling protein DRD1 in RNA-directed DNA methylation

In plants, the mechanism by which RNA can induce de novo cytosine methylation of homologous DNA is poorly understood. Cytosines in all sequence contexts become modified in response to RNA signals. Recent work has implicated the de novo DNA methyltransferases (DMTases), DRM1 and DRM2, in establishing RNA-directed methylation of the constitutive nopaline synthase promoter, as well as the DMTase MET1 and the putative histone deacetylase HDA6 in maintaining or enhancing CpG methylation induced by RNA. Despite the identification of enzymes that catalyze epigenetic modifications in response to RNA signals, it is unclear how RNA targets DNA for methylation. A screen for mutants defective in RNA-directed DNA methylation identified a novel putative chromatin-remodeling protein, DRD1. This protein belongs to a previously undefined, plant-specific subfamily of SWI2/SNF2-like proteins most similar to the RAD54/ATRX subfamily. In drd1 mutants, RNA-induced non-CpG methylation is almost eliminated at a target promoter, resulting in reactivation, whereas methylation of centromeric and rDNA repeats is unaffected. Thus, unlike the SNF2-like proteins DDM1/Lsh1 and ATRX, which regulate methylation of repetitive sequences, DRD1 is not a global regulator of cytosine methylation. DRD1 is the first SNF2-like protein implicated in an RNA-guided, epigenetic modification of the genome.     

Dynamics of DNA methylation in aging and Alzheimer's disease

Gene expression is modulated by epigenetic factors that come in varying forms, such as DNA methylation, histone modifications, microRNAs, and long noncoding RNAs. Recent studies reveal that these epigenetic marks are important regulatory factors in brain function. In particular, DNA methylation dynamics are found to be essential components of epigenetic regulation in the mammalian central nervous system. In this review, we provide an overview of the literature on DNA methylation in neurodegenerative diseases, with a special focus on methylation of 5-position of cytosine base (5mC) and hydroxymethylation of 5-position of cytosine base (5hmC) in the context of neurodegeneration associated with aging and Alzheimer's disease.     

Roles,and establishment,maintenance and erasing of the epigenetic cytosine methylation marks in plants

Heritable information in plants consists of genomic information in DNA sequence and epigenetic information superimposed on DNA sequence. The latter is in the form of cytosine methylation at CG, CHG and CHH elements (where H = A, T or C) and a variety of histone modifications in nucleosomes. The epialleles arising from cytosine methylation marks on the nuclear genomic loci have better heritability than the epiallelic variation due to chromatin marks. Phenotypic variation is increased manifold by epiallele comprised methylomes. Plants (angiosperms) have highly conserved genetic mechanisms to establish, maintain or erase cytosine methylation from epialleles. The methylation marks in plants fluctuate according to the cell/tissue/organ in the vegetative and reproductive phases of plant life cycle. They also change according to environment. Epialleles arise by gain or loss of cytosine methylation marks on genes. The changes occur due to the imperfection of the processes that establish and maintain the marks and on account of spontaneous and stress imposed removal of marks. Cytosine methylation pattern acquired in response to abiotic or biotic stress is often inherited over one to several subsequent generations. Cytosine methylation marks affect physiological functions of plants via their effect(s) on gene expression levels. They also repress transposable elements that are abundantly present in plant genomes. The density of their distribution along chromosome lengths affects meiotic recombination rate, while their removal increases mutation rate. Transposon activation due to loss of methylation causes rearrangements such that new gene regulatory networks arise and genes for microRNAs may originate. Cytosine methylation dynamics contribute to evolutionary changes. This review presents and discusses the available evidence on origin, removal and roles of cytosine methylation and on related processes, such as RNA directed DNA methylation, imprinting, paramutation and transgenerational memory in plants.     

High-resolution analysis of cytosine methylation in ancient DNA

Epigenetic changes to gene expression can result in heritable phenotypic characteristics that are not encoded in the DNA itself, but rather by biochemical modifications to the DNA or associated chromatin proteins. Interposed between genes and environment, these epigenetic modifications can be influenced by environmental factors to affect phenotype for multiple generations. This raises the possibility that epigenetic states provide a substrate for natural selection, with the potential to participate in the rapid adaptation of species to changes in environment. Any direct test of this hypothesis would require the ability to measure epigenetic states over evolutionary timescales. Here we describe the first single-base resolution of cytosine methylation patterns in an ancient mammalian genome, by bisulphite allelic sequencing of loci from late Pleistocene Bison priscus remains. Retrotransposons and the differentially methylated regions of imprinted loci displayed methylation patterns identical to those derived from fresh bovine tissue, indicating that methylation patterns are preserved in the ancient DNA. Our findings establish the biochemical stability of methylated cytosines over extensive time frames, and provide the first direct evidence that cytosine methylation patterns are retained in DNA from ancient specimens. The ability to resolve cytosine methylation in ancient DNA provides a powerful means to study the role of epigenetics in evolution.     

酵母模式生物研究表观遗传调控基因组稳定性的进展

基因组的遗传稳定性是维持正常的细胞复制、增殖和分化的关键。外源因素和内源因素造成的DNA损伤及其修复失败, 是各种遗传疾病发生的根本原因。表观遗传调控(包括DNA甲基化、组蛋白修饰和非编码RNA)在DNA损伤修复和细胞周期调控方面发挥着重要的作用, 也是维持基因组稳定性的基础。酵母作为单细胞真核生物, 是最早开展表观遗传学研究的物种之一, 特别是在DNA损伤修复和异染色质形成等方面的研究, 为揭示遗传稳定性的本质提供了理论依据。国际上前期以酵母为模式生物研究表观遗传学的报道主要集中于组蛋白修饰领域; 近期利用裂殖酵母作为模式生物研究RNAi指导的组蛋白修饰也有了一定的进展。文章以酵母作为模式生物, 论述了表观遗传修饰在维持基因组遗传稳定性中的研究进展、作用机制和今后的发展趋势。