基因组水平的组蛋白甲基化在乳腺肿瘤转化过程中的动态变化规律及调控机制

发布时间：2018-05-30 06:23

本文选题：乳腺癌 + 表观遗传组　；参考：《武汉大学》2016年博士论文

【摘要】：癌症是危害人类健康的重要疾病。肿瘤的早期诊断和治疗被认为是癌症的最佳的防治方式。越来越多的报道证实肿瘤发生过程中不仅伴随着基因组的突变,还包括表观遗传修饰的改变。本研究建立乳腺肿瘤发生的细胞模型来研究这一过程表观遗传修饰的变化及机制。本文在人源乳腺原代细胞中通过逆转录病毒感染的方法表达Large T antigen, TERT和RASV12三个蛋白,使其转化为肿瘤细胞；通过基因表达的分析,证实此模型较好的模拟了乳腺癌发生过程。在此模型中检测了15种组蛋白修饰的全局变化,发现H3K9me2和H3K9me3显著地梯度下降,并在乳腺癌组织验证了该结果。进一步通过高通量测序的方法,在基因组范围内分析H3K9me2、H3K9me3、H3K4me3、H3K27me3和基因表达的变化。H3K9me3的变化频繁发生在小片段区域,功能分析显示这些区域的基因多为转录因子,并且H3K9me3的整体水平下降影响了基因组的稳定性。H3K9me2变化的区域覆盖了很多癌症相关基因,并调控了基因的表达和转录起始位点区域的H3K4me3及H3K27me3水平；H3K9me2的变化在LOCKs (Large organized chromatin H3K9 modifications)区域更为显著,表现为LOCKs边缘区域富集了更多的癌症相关基因。进一步的研究发现组蛋白去甲基化酶KDM3A在乳腺癌细胞中高表达,能够促进乳腺癌细胞的增殖和肿瘤形成。通过高通量测序,发现KDM3A调控了癌症相关基因的表达和H3K9me2修饰水平,如MYC和BCL2,证明KDM3A是一个乳腺癌癌基因。综上所述,本文利用系统生物学方法来研究乳腺癌的发生过程,在表观遗传基因组水平描述了H3K9甲基化下降的规律,阐明了其与肿瘤发生的关系,找到了H3K9me2下降的因素KDM3A并鉴定为癌基因,研究了其调控机制。本研究找到了乳腺癌发生的早期分子标志,为临床早期诊断和药物靶点设计提供了新的思路和基础。
[Abstract]:Cancer is an important disease that endangers human health. The early diagnosis and treatment of cancer is considered to be the best way to prevent and cure cancer. More and more reports have confirmed that oncogenesis is accompanied not only by mutations in the genome, but also by epigenetic modification. In this study, a cell model of breast neoplasms was established to study the changes and mechanisms of epigenetic modification in this process. Three proteins, Large T antigen, TERT and RASV12, were expressed in human mammary gland primary cells by retrovirus infection, which were transformed into tumor cells. The analysis of gene expression confirmed that the model could simulate the process of breast cancer. In this model, the global changes of 15 histone modifications were detected, and the gradient of H3K9me2 and H3K9me3 were significantly decreased, and the results were verified in breast cancer tissues. Furthermore, by high-throughput sequencing, the changes of H3K9me2H3K9me3m3m3m3m3m3m3K4me3 and H3K27me3 gene expression occurred frequently in small fragment regions, and functional analysis showed that most of the genes in these regions were transcriptional factors, and H3K9me3 gene expression changes occurred frequently in small fragment regions, and functional analysis showed that most of the genes in these regions were transcriptional factors. And the overall decline in H3K9me3 levels affected the stability of the genome. H3K9me2 changes covered many cancer-related genes. The gene expression and the changes of H3K4me3 and H3K9me2 in the region of transcription initiation site were more significant in the LOCKs large organized chromatin H3K9 modifications region, which showed that more cancer-related genes were enriched in the marginal region of LOCKs. Further studies have found that histone demethylase KDM3A is highly expressed in breast cancer cells, which can promote the proliferation and tumor formation of breast cancer cells. By high-throughput sequencing, it was found that KDM3A regulated the expression of cancer-related genes and the level of H3K9me2 modification, such as MYC and BCL2, which proved that KDM3A was a breast cancer oncogene. To sum up, we use systems biology method to study the process of breast cancer, describe the law of H3K9 methylation decrease at the level of epigenetic genome, and elucidate its relationship with tumorigenesis. The factor of decreasing H3K9me2 KDM3A was identified as oncogene and its regulatory mechanism was studied. In this study, early molecular markers of breast cancer were found, which provided a new idea and basis for clinical early diagnosis and drug target design.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.9

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