人类基因组组蛋白修饰的相互作用及功能分析

发布时间：2019-01-29 06:37

【摘要】：表观遗传学修饰主要包括DNA甲基化、组蛋白修饰和miRNA等。其中，组蛋白修饰是在基因组水平上起到动态调控作用的主要修饰。目前，已经发现的组蛋白修饰种类多达百种以上，常见的组蛋白修饰类型主要包括甲基化、乙酰化等，大多位于组蛋白H3和H4上。研究表明组蛋白修饰酶的相互作用导致组蛋白修饰之间的相互作用。基于染色质修饰和基因组元件协同影响DNA甲基化这一生物学假设，开发了基于生物学机制的临近性算法以刻画它们对甲基化的作用，得到CpG位点的临近性谱。使用聚类分析得到8个与功能相关的CpG位点的聚类，聚类内有高度一致的功能和染色质修饰模式。贝叶斯网络分析推测出了相互作用的组蛋白修饰对（pairs），其中包括聚类共享和聚类特异的相互作用关系。为了进一步研究组蛋白修饰协同作用的功能效果，利用组蛋白H3尾巴上的两种代表性修饰（H3K4me3和H3K27me3）在干细胞分化中的相互作用的变化所带来的基因表达、染色质等变化进行分析。通过10个细胞系类型外加H1干细胞的组蛋白修饰数据，，分别研究了基因组水平上的干细胞分化前后的细胞类型的特异和一致的组蛋白修饰类型及分化过程中的变化模式。本课题发现的模式均与已有的文献报道相一致，例如GO富集显示的K4K27所定位的基因与发育过程有关。另外还发现使用组合式的组蛋白修饰模式对细胞特异性基因的识别有一定的效果，并且通过基因表达等数据进行了很好的验证。本研究对揭示新的组蛋白修饰协同调控基因表达的模式，以及研究变化的组蛋白修饰模式与功能的关系具有重要的意义。
[Abstract]:Epigenetic modification mainly includes DNA methylation, histone modification and miRNA. Histone modification is the main modification that plays a dynamic role in the genome level. At present, more than 100 kinds of histone modifications have been found. The common histone modification types include methylation, acetylation and so on, most of which are located on histone H3 and H4. Studies have shown that the interaction of histone modifying enzymes leads to the interaction between histone modifications. Based on the biological hypothesis that chromatin modification and genomic elements co-affect DNA methylation, an approach algorithm based on biological mechanism is developed to characterize their effects on methylation, and the proximity spectra of CpG sites are obtained. Eight functional CpG loci were clustered by cluster analysis, and there were highly consistent functional and chromatin modification patterns in the cluster. Bayesian network analysis inferred the interaction between interacting histone modification and (pairs), including cluster sharing and clustering specificity. In order to further study the functional effects of protein modification synergism, gene expression was induced by changes in the interaction of two representative modifications (H3K4me3 and H3K27me3) on the tail of histone H3 in stem cell differentiation. Chromatin changes were analyzed. Based on the histone modification data of 10 cell lines and H1 stem cells, the specific and consistent histone modification patterns of stem cells before and after differentiation were studied. The patterns found in this study are consistent with previous reports, for example, the genes located by K4K27 enriched by GO are related to the development process. It is also found that the combined histone modification pattern has a certain effect on the recognition of cell-specific genes and is well verified by gene expression data. This study is of great significance in revealing a new pattern of coregulation of histone modification gene expression and studying the relationship between histone modification mode and function.
【学位授予单位】：哈尔滨医科大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R346

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