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.     

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.     

Combinatorial chromatin modification patterns in the human genome revealed by subspace clustering

Chromatin modifications, such as post-translational modification of histone proteins and incorporation of histone variants, play an important role in regulating gene expression. Joint analyses of multiple histone modification maps are starting to reveal combinatorial patterns of modifications that are associated with functional DNA elements, providing support to the 'histone code' hypothesis. However, due to the lack of analytical methods, only a small number of chromatin modification patterns have been discovered so far. Here, we introduce a scalable subspace clustering algorithm, coherent and shifted bicluster identification (CoSBI), to exhaustively identify the set of combinatorial modification patterns across a given epigenome. Performance comparisons demonstrate that CoSBI can generate biclusters with higher intra-cluster coherency and biological relevance. We apply our algorithm to a compendium of 39 genome-wide chromatin modification maps in human CD4(+) T cells. We identify 843 combinatorial patterns that recur at >0.1% of the genome. A total of 19 chromatin modifications are observed in the combinatorial patterns, 10 of which occur in more than half of the patterns. We also identify combinatorial modification signatures for eight classes of functional DNA elements. Application of CoSBI to epigenome maps of different cells and developmental stages will aid in understanding how chromatin structure helps regulate gene expression.     

Discovering common combinatorial histone modification patterns in the human genome

Histone modifications play a crucial role in regulating gene expression and cell lineage determination and maintenance at the epigenetic level. To systematically investigate this phenomenon, this paper presented a statistical hybrid clustering algorithm to identify common combinatorial histone modification patterns. We applied the algorithm to 39 histone modification marks in human CD4 + T cells and detected 854 common combinatorial histone modification patterns. Our results could cover 211 (76.17%) patterns among 277 patterns identified by the tandem mass spectrometry experiments. Based on the frequency statistical analysis, it was found that the co-occurrence frequencies of 20 backbone modifications are greater than or close to 0.2 in the 854 patterns. we also found that 15 modifications (H2BK120ac, H4K91ac, H2BK20ac, etc.), three histone acetylations (H2AK9ac, H4K16ac, and H4K12ac) and five histone methylations (H3K79me1, H3K79me2, 3K79me3, H4K20me1, and H2BK5me1) were most likely prone to coexist respectively in these patterns. In addition, we found that DNA methylation tends to combine with histone acetylation rather than histone methylation.     

High fidelity epigenetic inheritance: Information theoretic model predicts threshold filling of histone modifications post replication

During cell devision, maintaining the epigenetic information encoded in histone modification patterns is crucial for survival and identity of cells. The faithful inheritance of the histone marks from the parental to the daughter strands is a puzzle, given that each strand gets only half of the parental nucleosomes. Mapping DNA replication and reconstruction of modifications to equivalent problems in communication of information, we ask how well enzymes can recover the parental modifications, if they were ideal computing machines. Studying a parameter regime where realistic enzymes can function, our analysis predicts that enzymes may implement a critical threshold filling algorithm which fills unmodified regions of length at most k. This algorithm, motivated from communication theory, is derived from the maximum à posteriori probability (MAP) decoding which identifies the most probable modification sequence based on available observations. Simulations using our method produce modification patterns similar to what has been observed in recent experiments. We also show that our results can be naturally extended to explain inheritance of spatially distinct antagonistic modifications.     

Genome-wide analysis of epigenetic dynamics across human developmental stages and tissues

Background

Epigenome is highly dynamic during the early stages of embryonic development. Epigenetic modifications provide the necessary regulation for lineage specification and enable the maintenance of cellular identity. Given the rapid accumulation of genome-wide epigenomic modification maps across cellular differentiation process, there is an urgent need to characterize epigenetic dynamics and reveal their impacts on differential gene regulation.

Methods

We proposed DiffEM, a computational method for differential analysis of epigenetic modifications and identified highly dynamic modification sites along cellular differentiation process. We applied this approach to investigating 6 epigenetic marks of 20 kinds of human early developmental stages and tissues, including hESCs, 4 hESC-derived lineages and 15 human primary tissues.

Results

We identified highly dynamic modification sites where different cell types exhibit distinctive modification patterns, and found that these highly dynamic sites enriched in the genes related to cellular development and differentiation. Further, to evaluate the effectiveness of our method, we correlated the dynamics scores of epigenetic modifications with the variance of gene expression, and compared the results of our method with those of the existing algorithms. The comparison results demonstrate the power of our method in evaluating the epigenetic dynamics and identifying highly dynamic regions along cell differentiation process.

     

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.     

基于ChIP-seq的差异组蛋白修饰区域的筛选

组蛋白修饰是在基因组水平上起到重要调控作用的表观遗传修饰,随着ChIP-Seq的广泛使用,高通量数据的积累,为从全基因组研究组蛋白修饰模式奠定了基础。但目前缺乏在多样本间筛选疾病相关的调控区域的方法,因而本文开发了一种多细胞系的差异筛选算法来识别差异组蛋白修饰区域。本文通过窗口移动法来估计组蛋白修饰水平,并根据信息熵理论定量各个细胞系之间的差异。基于随机背景来确定差异显著性阈值。利用此算法来筛选人类全基因组9个细胞系间H3K4me3差异的区域,结果显示这些区域显著富集在基因启动子上和其他重要的染色质状态上,且与先前人们发现的活性启动子染色质状态显著重叠。通过文献挖掘进一步证实了与白血病相关的基因组标记。这些结果表明基于熵的策略可有效地挖掘多细胞系间以及与疾病相关的差异组蛋白修饰。