Prediction of regulatory elements in mammalian genomes using chromatin signatures

Background  

Recent genomic scale survey of epigenetic states in the mammalian genomes has shown that promoters and enhancers are correlated with distinct chromatin signatures, providing a pragmatic way for systematic mapping of these regulatory elements in the genome. With rapid accumulation of chromatin modification profiles in the genome of various organisms and cell types, this chromatin based approach promises to uncover many new regulatory elements, but computational methods to effectively extract information from these datasets are still limited.     

How imprinting centres work

Imprinted genes tend to be clustered in the genome. Most of these clusters have been found to be under the control of discrete DNA elements called imprinting centres (ICs) which are normally differentially methylated in the germline. ICs can regulate imprinted expression and epigenetic marks at many genes in the region, even those which lie several megabases away. Some of the molecular and cellular mechanisms by which ICs control other genes and regulatory regions in the cluster are becoming clear. One involves the insulation of genes on one side of the IC from enhancers on the other, mediated by the insulator protein CTCF and higher-order chromatin interactions. Another mechanism may involve non-coding RNAs that originate from the IC, targeting histone modifications to the surrounding genes. Given that several imprinting clusters contain CTCF dependent insulators and/or non-coding RNAs, it is likely that one or both of these two mechanisms regulate imprinting at many loci. Both mechanisms involve a variety of epigenetic marks including DNA methylation and histone modifications but the hierarchy of and interactions between these modifications are not yet understood. The challenge now is to establish a chain of developmental events beginning with differential methylation of an IC in the germline and ending with imprinting of many genes, often in a lineage dependent manner.     

Broad Chromatin Domains: An Important Facet of Genome Regulation

Chromatin composition differs across the genome, with distinct compositions characterizing regions associated with different properties and functions. Whereas many histone modifications show local enrichment over genes or regulatory elements, marking can also span large genomic intervals defining broad chromatin domains. Here we highlight structural and functional features of chromatin domains marked by histone modifications, with a particular emphasis on the potential roles of H3K27 methylation domains in the organization and regulation of genome activity in metazoans.     

Genome-wide enhancer prediction from epigenetic signatures using genetic algorithm-optimized support vector machines

The chemical modification of histones at specific DNA regulatory elements is linked to the activation, inactivation and poising of genes. A number of tools exist to predict enhancers from chromatin modification maps, but their practical application is limited because they either (i) consider a smaller number of marks than those necessary to define the various enhancer classes or (ii) work with an excessive number of marks, which is experimentally unviable. We have developed a method for chromatin state detection using support vector machines in combination with genetic algorithm optimization, called ChromaGenSVM. ChromaGenSVM selects optimum combinations of specific histone epigenetic marks to predict enhancers. In an independent test, ChromaGenSVM recovered 88% of the experimentally supported enhancers in the pilot ENCODE region of interferon gamma-treated HeLa cells. Furthermore, ChromaGenSVM successfully combined the profiles of only five distinct methylation and acetylation marks from ChIP-seq libraries done in human CD4⁺ T cells to predict ∼21 000 experimentally supported enhancers within 1.0 kb regions and with a precision of ∼90%, thereby improving previous predictions on the same dataset by 21%. The combined results indicate that ChromaGenSVM comfortably outperforms previously published methods and that enhancers are best predicted by specific combinations of histone methylation and acetylation marks.     

Epigenetic control of plant immunity

In eukaryotic genomes, gene expression and DNA recombination are affected by structural chromatin traits. Chromatin structure is shaped by the activity of enzymes that either introduce covalent modifications in DNA and histone proteins or use energy from ATP to disrupt histone–DNA interactions. The genomic ‘marks’ that are generated by covalent modifications of histones and DNA, or by the deposition of histone variants, are susceptible to being altered in response to stress. Recent evidence has suggested that proteins generating these epigenetic marks play crucial roles in the defence against pathogens. Histone deacetylases are involved in the activation of jasmonic acid‐ and ethylene‐sensitive defence mechanisms. ATP‐dependent chromatin remodellers mediate the constitutive repression of the salicylic acid‐dependent pathway, whereas histone methylation at the WRKY70 gene promoter affects the activation of this pathway. Interestingly, bacterial‐infected tissues show a net reduction in DNA methylation, which may affect the disease resistance genes responsible for the surveillance against pathogens. As some epigenetic marks can be erased or maintained and transmitted to offspring, epigenetic mechanisms may provide plasticity for the dynamic control of emerging pathogens without the generation of genomic lesions.     

通过系统分析揭示组蛋白修饰模式与转录因子结合之间的关联

转录因子对顺势调控元件的选择性结合,在哺乳动物细胞类型特异的基因表达中扮演重要的角色.这个过程受到染色质表观遗传状态的潜在调控.近期,染色质免疫共沉淀结合测序的研究提供了大量泛基因组水平的数据,阐述转录因子结合以及组蛋白修饰的位点,这为系统地研究转录因子和表观遗传标记之间的空间及调控关系提供了基础.该研究对公共数据库中的染色质免疫共沉淀结合测序数据进行整合分析,涉及5个细胞系中的85种转录因子、9种组蛋白修饰,目的是研究转录因子结合位点与组蛋白修饰模式以及基因表达在泛基因组水平上的关联.作者发现,不同转录因子与组蛋白修饰的共定位模式高度一致,并且组蛋白修饰在距离转录因子结合位点约500碱基对的位置富集.作者还发现,转录因子结合位点的占有率与活性组蛋白修饰的水平和双峰模式正相关,并且启动子区域组蛋白修饰的双峰和共定位模式和基因的高转录水平相一致.组蛋白修饰模式、转录因子结合位点的占有率与基因转录之间的关联暗示了细胞可能利用的基因表达调控机制.     

Crosstalk between histone modifications maintains the developmental pattern of gene expression on a tissue-specific locus

Genome wide studies have provided a wealth of information related to histone modifications. Particular modifications, which can encompass both broad and discrete regions, are associated with certain genomic elements and gene expression status. Here we focus on how studies on the ß-globin gene cluster can complement the genome wide effort through the thorough dissection of histone modifying protein crosstalk. The ß-globin locus serves as a model system to study both regulation of gene expression driven at a distance by enhancers and mechanisms of developmental switching of clustered genes. We investigate recent studies, which uncover that histone methyltransferases, recruited at the ß-globin enhancer, control gene expression by long range propagation on chromatin. Specifically, we focus on how seemingly antagonistic complexes, such as those including MLL2, G9a and UTX, can cooperate to functionally regulate developmentally controlled gene expression. Finally, we speculate on the mechanisms of chromatin modifying complex propagation on genomic domains.     

Epigenetic marks in the <Emphasis Type="Italic">Hyacinthus orientalis</Emphasis> L. mature pollen grain and during in vitro pollen tube growth

During the sexual reproduction of flowering plants, epigenetic control of gene expression and genome integrity by DNA methylation and histone modifications plays an important role in male gametogenesis. In this study, we compared the chromatin modification patterns of the generative, sperm cells and vegetative nuclei during Hyacinthus orientalis male gametophyte development. Changes in the spatial and temporal distribution of 5-methylcytosine, acetylated histone H4 and histone deacetylase indicated potential differences in the specific epigenetic state of all analysed cells, in both the mature cellular pollen grains and the in vitro growing pollen tubes. Interestingly, we observed unique localization of chromatin modifications in the area of the generative and the vegetative nuclei located near each other in the male germ unit, indicating the precise mechanisms of gene expression regulation in this region. We discuss the differences in the patterns of the epigenetic marks along with our previous reports of nuclear metabolism and changes in chromatin organization and activity in hyacinth male gametophyte cells. We also propose that this epigenetic status of the analysed nuclei is related to the different acquired fates and biological functions of these cells.     

Evidence for sequence biases associated with patterns of histone methylation

ABSTRACT: BACKGROUND: Combinations of histone variants and modifications, conceptually representing a histone code, have been proposed to play a significant role in gene regulation and developmental processes in complex organisms. While various mechanisms have been implicated in establishing and maintaining epigenetic patterns at specific locations in the genome, they are generally believed to be independent of primary DNA sequence on a more global scale. RESULTS: To address this systematically in the case of the human genome, we have analyzed primary DNA sequences underlying 19 different methylated histones in human primary T-cells. We report that sequence alone can accurately predict the location of most of these histone marks genome-wide in this cell type. Furthermore, the sequence features responsible for such predictions are distinct for different groups of histone marks. CONCLUSIONS: These findings support the existence of a genomic code for histone modification associated with gene expression and chromatin programming, and they suggest that the mechanisms responsible for global histone modifications may interpret genomic sequence in various ways.