肿瘤细胞中Jhdm1b代谢调控功能的系统生物学研究

发布时间：2018-04-19 19:46

本文选题：代谢组学 + 组蛋白赖氨酸甲基化　；参考：《中国科学技术大学》2015年博士论文

【摘要】：代谢重编程,如沃伯格效应和谷氨酰胺分解,在人类的原发性肿瘤和转移性肿瘤中均为一种普遍现象。为了满足因快速生长而急剧增加的能量与物质需要,肿瘤细胞往往倾向于以更快速的方式利用葡萄糖和谷氨酰胺等营养物质,而忽略利用效率。表观遗传的改变在肿瘤发育和生长中也起到了关键性的作用。最近的研究表明,以DNA和组蛋白修饰为代表的表观遗传调控可以影响细胞的代谢状态。赖氨酸甲基化是组蛋白修饰的重要组成部分,而有报道称,影响赖氨酸甲基化状态的组蛋白赖氨酸甲基转移酶和去甲基化酶都在细胞代谢调控中扮演了重要角色。 Jhdmlb是一个组蛋白赖氨酸去甲基化酶。它是一个Jhdm家族成员,可以对H3K4me3和H3K36me2进行去甲基化,而且在许多癌症细胞中高表达。Jhdmlb在调控细胞生长和凋亡过程中发挥了重要功能,而最近的研究显示,Jhdmlb和细胞代谢调控关系密切,芯片实验证明Jhdmlb超过50%的下游基因功能都与细胞代谢有关。其中RIP3是一个苏氨酸／丝氨酸蛋白激酶,它可以直接调控谷氨酸合酶、谷氨酸脱氢酶、糖原磷酸化酶等代谢相关酶。尽管前人已经发现了Jhdmlb和细胞代谢有关,但目前仍然缺乏针对Jhdmlb的代谢调控机制的系统性研究。在本文中,我们建立了基于核磁共振波谱和气相色谱-质谱联用的哺乳动物细胞13C稳定同位素代谢组学分析平台,并利用这一技术系统研究了Jhdmlb被敲低后与PLKO.1对照组HeLa细胞的中心代谢网络的差异。我们的实验证明了Jhdmlb是一个RIP3依赖性的肿瘤细胞代谢调控因子。这一发现有助于探索癌症中的组蛋白甲基化与代谢调控的关系,为癌症治疗提供了新的思路。
[Abstract]:Metabolic reprogramming, such as the Warburg effect and glutamine decomposition, is a common phenomenon in human primary and metastatic tumors. In order to meet the rapidly increasing energy and material needs due to rapid growth, tumor cells tend to use nutrients such as glucose and glutamine more quickly, while neglecting the utilization efficiency. Epigenetic changes also play a key role in tumor development and growth. Recent studies have shown that epigenetic regulation, represented by DNA and histone modification, can affect the metabolic state of cells. Lysine methylation is an important part of histone modification, and it has been reported that histone lysine methyltransferase and demethylase play an important role in the regulation of cell metabolism. Jhdmlb is a histone lysine demethylase. It is a member of the Jhdm family that demethylates H3K4me3 and H3K36me2, and plays an important role in regulating cell growth and apoptosis by overexpression of .Jhdmlb in many cancer cells. Recent studies have shown that Jhdmlb is closely related to the regulation of cell metabolism. Microarray experiments have shown that over 50% of the downstream gene function of Jhdmlb is related to cell metabolism. RIP3 is a threonine / serine protein kinase, which can directly regulate the metabolism related enzymes such as glutamate synthase, glutamate dehydrogenase, glycogen phosphorylase and so on. Although Jhdmlb has been found to be related to cellular metabolism, there is still no systematic study on the metabolic regulation mechanism of Jhdmlb. In this paper, we have established a stable isotope metabonomics analysis platform for mammalian cells based on nuclear magnetic resonance spectroscopy (NMR) and gas chromatography-mass spectrometry (GC-MS). The difference of central metabolic network between HeLa cells after Jhdmlb knockout and PLKO.1 control was studied by using this technique. Our experiments have demonstrated that Jhdmlb is a RIP3-dependent metabolic regulator of tumor cells. The findings are helpful to explore the relationship between histone methylation and metabolic regulation in cancer and provide new ideas for cancer treatment.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.2

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