Environmental chemical stressors as epigenome modifiers: a new horizon in assessment of toxicological effects

In eukaryotic cells, chromatin transformation from euchromatin into heterochromatin as a means of controlling gene expression and replication has been known as the ‘‘accessibility hypothesis' '. The interplay of epigenetic changes including histone modifications, DNA methylation, RNA interference(RNAi) and other func- tional epigenetic components are intricate. It is believed that these changes are well-programmed, inherited and can be modified by environmental contaminant stressors. Environmentally-driven epigenetic alterations during development, e.g. embryonic, foetal or neonatal stage, may influence disease susceptibility in adulthood. Therefore, understanding how epigenome modifications develop in response to environmental chemicals and, how epigenetic-xenobiotic interactions influence human health will shed new insights into gene-environment interactions in the epidemiology of several diseases including cancer. In this review, we consider studies of chemical modifiers including nutritional and xenobiotic effects on epigenetic components in vitro or in vivo. By examining the most-studied epigenome modifications and how their respective roles are interlinked, we highlight the central role of xenbiotic- modified epigenetic mechanisms. A major requirement will be to study and understand effects following environmentally-relevant exposures. We suggest that the study of epigenetic toxicology will open up new opportunities to devise strategies for the prevention or treatment of at-risk populations.     

The role of histones and their modifications in the informative content of chromatin

It is traditionally accepted that the DNA sequence cannot by itself explain all the mechanisms necessary for the development of living beings, especially in eukaryotes. Indeed part of the information used in these processes is stored in other ways, generally called epigenetic, whose molecular mechanisms are mostly unknown. The ultimate explanation for them might reside in the non-DNA moiety of chromatin which may play an active role in heredity (chromatin information). Histones are the universal structural component of chromatin. However, recent studies strongly suggest that histones, and their modifications — especially the reversible acetylation of lysines — may act as a recognition signal for regulatory proteins and they may participate, for this reason, in gene regulation. This type of information could be maintained through its replication and, ultimately, it could form the molecular basis of certain processes related to the development of the eukaryotic organisms.     

Mass spectrometry-based proteomics in the life sciences

Over the last 20 years, mass spectrometrybased proteomics has become an indispensable tool in the cellular and molecular life sciences. This has been enabled by the soft ionisation techniques of electrospray and matrix-assisted laser desorption-ionisation, which allow the gentle ionisation and vaporisation of large, thermally labile biomolecules. Innovative instrumentation designs and biochemical strategies have brought success in the large-scale identification and quantification of proteins, as well as the characterisation of their complexes and post-translational modifications. This review describes the instrumentation used for proteomics research. It presents an overview of the current applications of mass spectrometry-based proteomics to the cellular and molecular life sciences, and discusses challenges that exist for research in the future.Received 7 January 2005; accepted 27 January 2005     

Emerging connections between DNA methylation and histone acetylation

Modifications of both DNA and chromatin can affect gene expression and lead to gene silencing. Evidence of links between DNA methylation and histone hypoacetylation is accumulating. Several proteins that specifically bind to methylated DNA are associated with complexes that include histone deacetylases (HDACs). In addition, DNA methyltransferases of mammals appear to interact with HDACs. Experiments with animal cells have shown that HDACs are responsible for part of the repressive effect of DNA methylation. Evidence was found in Neurospora that protein acetylation can in some cases affect DNA methylation. The available data suggest that the roles of DNA methylation and histone hypoacetylation, and their relationship with each other, can vary, even within an organism. Some open questions in this emerging field that should be answered in the near future are discussed.     

Chromatin assembly during S phase: contributions from histone deposition, DNA replication and the cell division cycle

During S phase of the eukaryotic cell division cycle, newly replicated DNA is rapidly assembled into chromatin. Newly synthesised histones form complexes with chromatin assembly factors, mediating their deposition onto nascent DNA and their assembly into nucleosomes. Chromatin assembly factor 1, CAF-1, is a specialised assembly factor that targets these histones to replicating DNA by association with the replication fork associated protein, proliferating cell nuclear antigen, PCNA. Nucleosomes are further organised into ordered arrays along the DNA by the activity of ATP-dependent chromatin assembly and spacing factors such as ATP-utilising chromatin assembly and remodelling factor ACF. An additional level of controlling chromatin assembly pathways has become apparent by the observation of functional requirements for cyclin-dependent protein kinases, casein kinase II and protein phosphatases. In this review, we will discuss replication-associated histone deposition and nucleosome assembly pathways, and we will focus in particular on how nucleosome assembly is linked to DNA replication and how it may be regulated by the cell cycle control machinery.     

组蛋白甲基化修饰在小鼠早期胚胎发育中的建立与调控

 组蛋白修饰作为重要的表观遗传修饰，在调控胚胎基因表达、胚胎细胞的命运决定及胚胎基因组的稳定性等方面均起了很重要的作用。微量测序技术的发展使从全基因组水平上检测植入前胚胎的组蛋白修饰成为可能。综述了近年来利用该技术对小鼠早期胚胎发育过程中的组蛋白甲基化修饰研究的最新进展，总结了在胚胎基因激活及第一次细胞分化过程中组蛋白H3K4me3和H3K27me3修饰不同的建立和动态变化趋势，这些研究为探索胚胎发育和细胞分化的表观调控机制奠定了基础。     

基于广义线性模型的基因表达水平预测

组蛋白修饰是生物体中普遍存在的一种现象,能够以不同的调控方式影响基因表达,且随着高通量测序技术的飞速发展,大量的测序数据使得探究组蛋白修饰信号与基因表达水平之间的内在联系成为可能.由于基因表达数据存在零膨胀现象,提出了一种基于广义线性模型框架的主从模型,能够以较高精度从组蛋白修饰信号预测基因表达水平.首先通过人类全基因组注释文件中的基因位点信息,筛选出包含完整基因位点信息的表达数据;其次,根据基因位点信息,定位并提取出组蛋白修饰数据中基因特定位点的特征信息,构建设计矩阵;最后结合响应变量数据零膨胀的特点,构建主从模型,以GM12878细胞系为例,与现有的多种回归算法进行对比,验证了所提模型的有效性.     

六硝基六氮杂异伍兹烷的分子络合物

通过对多种有机溶剂的筛选，发现五种溶剂分子能与六硝基六氮杂异伍兹烷生成分子络合物，二甲基亚砜与ＨＮＩＷ生成等摩尔络合物；二氧六环与ＨＮＩＷ生成３：２络合物；Ｎ，Ｎ－二甲基甲酰胺，γ－丁内酯与ＨＮＩＷ都生成２：１络合物；六甲基磷酰三胺与ＨＮＩＷ生成３：１络合物。还提出了某些结构性质。