植物表观遗传修饰与病原菌胁迫应答研究进展

真核生物基因表达受到染色质结构的调控,组蛋白与DNA的共价修饰构成表观遗传标签,并在植物胁迫应答如防御病原菌侵染过程中起重要作用.病原菌侵染可引起基因组整体DNA甲基化模式变化及胁迫应答基因的位点特异性去甲基化,导致植物抗性基因表达上调或下调,并进一步调控植物对病原菌的胁迫应答;组蛋白去乙酰化酶HDAC通过茉莉酸途径增强植物对病原菌的胁迫应答;此外,染色质重塑复合物Swr1复合体通过识别DNA基元和组蛋白乙酰化修饰状态靶向基因启动子,负调控SA敏感基因.该文从DNA甲基化、组蛋白乙酰化、甲基化修饰,染色质重塑等方面着重阐述植物与病原菌互作过程中发生的主要事件的分子基础及其研究进展.     

DNA methylation in animal development

Nuclear transfer experiments have demonstrated that epigenetic mechanisms operate to limit gene expression during animal development. In somatic cells, silenced genes are associated with defined chromatin states which are characterised by hypermethylation of DNA, hypoacetylation of histones and specific patterns of methylation at distinct residues of the N-terminal tails of histone H3 and H4. This review describes the role of the DNA methylation-mediated repression system (Dnmt1's, MeCPs and MBDs and associated chromatin remodelling activities) in animal development. DNA methylation is essential for normal vertebrate development but has distinct regulatory roles in non-mammalian and mammalian vertebrates. In mammals, DNA methylation has an additional role in regulating imprinting. This suggests that epigenetic regulation is plastic in its application and should be considered in a developmental context that may be species specific.     

植物DNA甲基化调控因子研究进展

DNA甲基化是重要的植物基因组表观遗传修饰。植物中DNA甲基化的建立与维持是由多个调控因子协同作用的结果。不同的甲基转移酶类能直接作用于不同位点胞嘧啶甲基化, 其中MET1主要负责保持原初CG位点的甲基化, CMT3主要负责保持CNG位点的甲基化, 并由DRM与CMT3的协同从头甲基化作用来补偿其他相关序列的甲基化。这些甲基转移酶与染色质重塑解旋酶和组蛋白修饰因子协同改变染色质的结构, 行使表观遗传的功能。DNA转葡糖基酶有去甲基化活性从而减轻基因沉默。文章综述了以上植物DNA甲基化调控因子的生物学功能及其之间的相互作用和近年来的研究进展, 以更好的理解DNA甲基化的建立、保持和去除的机制。     

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome‐wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA‐ and histone‐modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.     

DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling

DNA methylation is a major epigenetic factor that has been postulated to regulate cell lineage differentiation. We report here that conditional gene deletion of the maintenance DNA methyltransferase I (Dnmt1) in neural progenitor cells (NPCs) results in DNA hypomethylation and precocious astroglial differentiation. The developmentally regulated demethylation of astrocyte marker genes as well as genes encoding the crucial components of the gliogenic JAK-STAT pathway is accelerated in Dnmt1-/- NPCs. Through a chromatin remodeling process, demethylation of genes in the JAK-STAT pathway leads to an enhanced activation of STATs, which in turn triggers astrocyte differentiation. Our study suggests that during the neurogenic period, DNA methylation inhibits not only astroglial marker genes but also genes that are essential for JAK-STAT signaling. Thus, demethylation of these two groups of genes and subsequent elevation of STAT activity are key mechanisms that control the timing and magnitude of astroglial differentiation.     

Structural and functional features of the 5-methylcytosine distribution in the eukaryotic genome

DNA methylation is an integral part of the mechanism of a remodeling and modification of the chromatin structure. The global complex net of chromatin modification and remodeling reactions is still to be determined, and studies of the mechanisms controlling the epigenetic processes of histone modification and DNA methylation are in their infancy. Cytosine methylation occurs predominantly in CpG sequences of the eukaryotic genome, and it also takes place at symmetric CpHpG and nonsymmetric CpHpH sites (where H is A, T, or C). The modification efficiency of the three types of DNA methylation sites depends on their genomic localization. Different regions of the eukaryotic genome are remarkable for their methylation features: CpG-islands, CpG-island shores, differentially methylated regions of imprinted genes, and regions of nonalternative site-specific modification. The three canonical sites (CpG, CpHpG, and CpHpH) differ in DNA methylation efficiency depending on their nucleotide context. An epigenetic code of DNA methylation can be assumed with context differences playing a specific functional role. The review summarizes the main up-to-date data on the structural and functional features of site-specific cytosine methylation in eukaryotic genomes. Pathogenesis-related alterations in the methylation pattern of the eukaryotic genome are considered.     

Regulation of imprinted DNA methylation

DNA methylation is an essential enzymatic modification in mammals. This common epigenetic mark occurs predominantly at the fifth carbon of cytosines within the palindromic dinucleotide 5'-CpG-3'. The majority of methylated CpGs are located within repetitive elements including centromeric repeats, satellite sequences and gene repeats encoding ribosomal RNAs. CpG islands, frequently located at the 5' end of genes, are typically unmethylated. DNA methylation also occurs at imprinted genes which exhibit parent-of-origin-specific patterns of methylation and expression. Imprinted methylation at differentially methylated domains (DMDs) is one of the regulatory mechanisms controlling the allele-specific expression of imprinted genes. Proper control of DNA methylation is needed for normal development and loss of methylation control can contribute to initiation and progression of tumorigenesis (reviewed in Plass and Soloway, 2002). Because patterns of imprinted DNA methylation are highly reproducible, imprinted loci make useful models for studying regulation of DNA methylation and may provide insights into how this regulation goes awry in cancer. Here, we review what is currently known about the mechanisms regulating imprinted DNA methylation. We will focus on cis-acting DNA sequences, trans-acting protein factors and the possible involvement of RNAs in control of imprinted DNA methylation.     

Prenatal nutrition and the risk of adult obesity: Long-term effects of nutrition on epigenetic mechanisms regulating gene expression

Solid epidemiological evidence indicates that part of the risk of obesity in adulthood could be programmed during prenatal development by the quality of maternal nutrition. Nevertheless, the molecular mechanisms involved are mostly unknown, which hinders our capacity to develop effective intervention policies. Here, we discuss the hypothesis that mechanisms underlying prenatal programming of adult risk are epigenetic and sensitive to environmental cues such as nutrition. While the information encoded in DNA is essentially stable, regulatory epigenetic mechanisms include reversible, covalent modifications of DNA and chromatin, such as methylation, acetylation etc. It is known that dietary availability of methyl donors has an impact on the patterns of gene expression by affecting DNA methylation at regulatory regions, a likely basis for reprogramming developmental plasticity. The Agouti and Axin-fused genes, as well as the embryonic growth factor IGF2/H19 locus are examples of diet-induced modulation of phenotypic traits by affecting methylation of gene-regulatory regions. Recent work has evidenced an unsuspected role for chromatin as metabolic sensor. Chromatin is susceptible to a number of post-translational modifications that modulate gene expression, among them the GlcNAcylation of histone proteins and other epigenetic regulators. Intracellular levels of the precursor molecule UDP-GlcNAc, and hence the degree of global chromatin GlcNAcylation, depend on the energetic state of the cell, making GlcNAcylation a functional link between nutrition and regulation of gene expression. Dietary interference with these regulatory mechanisms could effectively counteract the early-life programming of adult risk.     

Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation

Linker histone H1 plays an important role in chromatin folding in vitro. To study the role of H1 in vivo, mouse embryonic stem cells null for three H1 genes were derived and were found to have 50% of the normal level of H1. H1 depletion caused dramatic chromatin structure changes, including decreased global nucleosome spacing, reduced local chromatin compaction, and decreases in certain core histone modifications. Surprisingly, however, microarray analysis revealed that expression of only a small number of genes is affected. Many of the affected genes are imprinted or are on the X chromosome and are therefore normally regulated by DNA methylation. Although global DNA methylation is not changed, methylation of specific CpGs within the regulatory regions of some of the H1 regulated genes is reduced. These results indicate that linker histones can participate in epigenetic regulation of gene expression by contributing to the maintenance or establishment of specific DNA methylation patterns.     

Lessons from two human chromatin diseases, ICF syndrome and Rett syndrome

Spatial organisation of DNA into chromatin profoundly affects gene expression and function. The recent association of genes controlling chromatin structure to human pathologies resulted in a better comprehension of the interplay between regulation and function. Among many chromatin disorders we will discuss Rett and immunodeficiency, centromeric instability and facial anomalies (ICF) syndromes. Both diseases are caused by defects related to DNA methylation machinery, with Rett syndrome affecting the transduction of the repressive signal from the methyl CpG binding protein prototype, MeCP2, and ICF syndrome affecting the genetic control of DNA methylation, by the DNA methyltransferase DNMT3B. Rather than listing survey data, our aim is to highlight how a deeper comprehension of gene regulatory web may arise from studies of such pathologies. We also maintain that fundamental studies may offer chances for a therapeutic approach focused on these syndromes, which, in turn, may become paradigmatic for this increasing class of diseases.