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The Analysis on the Combinatorial Patterns of Histone Modifications in Saccharomyces Cerevisiae

Author: CuiXiangJun
Tutor: LiHong
School: Inner Mongolia University
Course: Theoretical Physics
Keywords: Histone modification Combinatorial pattern Gene transcriptlevel Bayesian network Causal relationship
CLC: Q936
Type: PhD thesis
Year: 2012
Downloads: 78
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Abstract


After Human Genome Project was completed, a large amount of DNA sequence data was obtained. Based on the data, the researchers develop a great deal of work in the terms of gene expression. We gradually realize that the regulation on genomic DNA is very complex in the course of endless research. The relevant research results show that other hereditable biological factors affect gene expression besides DNA sequence. This kind of effects is called epigenetic regulation. Till then, epigenetics emerges as the times require. These informations on epigenetic regulation mainly focus on several aspects:histone modification, nucleosome positioning, chromatin remodeling, DNA methylation and non-coding RNA etc. These factors can interact on each other and codetermine complex life process.Histone modifications are an important research topics of the information on epigenetic regulatory. Histone modifications occur in the N-terminus of histones of nucleosomes under the action of relevant modifying enzymes. The common covalent modifications include methylation, acetylation and phosphorylation etc. Differnet histone modifications play different roles in gene expression. Various models, including the histone code, the signalling network and the charge neutralization model, have been proposed to account for the function of histone modifications. Strahl and Allis put forward "histone code" hypothesis in2000. The hypothesis suggests that single one histone modification cannot usually play its role. Multiple different covalent modifications at the terminus of one or multiple histones play their roles sequentially or combine together, and form a cascade of modifications. They together play a role cooperatelly or antagonistically and affect gene expression. After histone code was put forward, combinatorial patterns of histone modifications become a focal point of research in the field of gene expression.Based on the idea of histone code, the combinatorial patterns of histone modifications in Saccharomyces cerevisiae were studied in this paper. In addition, the action relationships of histone modifications were put forward. The underlying mechanisms on the causal and combinatorial relationships were discussed from modifying enzyme view at molecular biology level. The main contributions are summarized as follows:1. Base on the histone modification data of Saccharomyces cerevisiae obtained and transcriptional start sites (TSS) confirmed, on one hand, in order to get a general idea of the change trend of histone modifications around TSS; on the other hand, to verify the histone modification data filtered, the distribution patterns of modifications were studied at promoter regions and coding regions. The results of distribution patterns of some classical mosifications (for example H3K4me3, H3K4me2and H3K4mel) show that the data filtered is accurate. The modification levels of all histone modifications change obviously around TSS. The modification levels are almost the lowest at TSS. The modifications gradually boost up flank TSS. The modification levels gradually decrease near the end of the coding regions.2. In order to analyze the network of histone modifications constructed, we firstly studied the correlation of12histone modifications. Moreover, for the regions of TSS-1kb studied mainly, the Pearson correlation analysis on the modifications was performed too. The results show that12histone modifications are divided into two groups strongly correlated to each other on the base of correlation coefficients. One group corresponds to transcription enhancing modifications (group A) and the other one corresponds to transcription repressing or non-significant correlation modifications (group B). Group A includes seven modifications (H2AK7Ac, H3K14Ac, H3K9Ac, H4K5Ac, H3K18Ac, H4K12Ac and H3K4Me3) and group B includes five modifications (H3K4Mel, H2BK16Ac, H3K4Me2, H4K16Ac and H4K8Ac). The result of cluster for modifications based on transcript levels is consistent with the Pearson correlation analysis.3. Some histone modifying enzymes can be binded with other modifications by protein domains of its own. So the causal correlations are established between histone modifications catalyzed by the enzymes and the modifications used as binding sites. Based on this, the modification combinations can be formed between the two modifications. According to the thoughts mentioned above, the combinatorial patterns of histone modifications were studied by Bayesian network for method. Bayesian network can indicate the causal relationship among multiple mosifications within a combinatorial pattern.23combinatorial patterns were determined for12histone modifications in this study. Normally, there are stronger correlations among several modifications within a combinatorial pattern and these modifications are within a correlation group. In addition, a part of histone modification combinations were analyzed at the level of molecular structure of modifying enzymes.4. In order to understand the difference in the causal relationships of histone modifications under the circumstances of different transcript levels, the Bayesian network for the genes with high transcript levels (H-network) and the Bayesian network for the genes with low transcript levels (L-network) were constructed based on deleting gradually lowly-transcribed and highly-transcribed genes. The modification relationships within H-network are found to be more stable and less changeable. It suggests that more modification combinations play biological roles when gene transcript levels are high. Four kinds of modification combinations (H2BK16Ac→H3K4Me3, H3K14Ac→H3K4Me3, H4K12Ac→H3K18Ac and H2AK7Ac→H3K14Ac) always play their roles. Their functions do not depend on transcript levels. These modification combinations are necessary to gene transcription. Moreover, the action relationship model of histone modifications was put forward on the base of the stable pathways within two networks. The "open" and "close" of the terminal modifications in two networks were mutually exclusive. Because there are causal relationships, the relationships among the modifications which reside on the top layer of network may have impacts on the relationships of downstream modifications. Meanwhile, the effects play the roles in the relationship between terminal modifications and Pol Ⅱ. The processes of how the causal relationships among modifications on the top layer of network affect downstream modifications were analyzed further in this paper.

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CLC: > Biological Sciences > Microbiology > Microbial biochemistry
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