人脂肪干细胞成脂分化过程中重要调控因子的识别与鉴定

发布时间：2018-05-02 20:01

本文选题：人脂肪干细胞(hASC) + 成脂分化　；参考：《浙江大学》2017年硕士论文

【摘要】：人类脂肪干细胞(hASC)自2001年被Zuk PA发现并验证后一直备受关注,与骨髓来源的间充质干细胞(BM-MSC)相比,其来源广、易获得、产量高等优点使其迅速成为干细胞研究以及再生医学研究的重点。从脂肪干细胞分化为脂肪细胞的成脂分化过程在维持脂肪组织稳态、脂质与糖类吸收的稳态、系统代谢等方面起着重要作用,因此,研究成脂分化的具体机制具有重大的生物学和生物医学意义。然而,除成脂分化后期相关的机制外,都不十分清楚,尤其是早期的成脂分化机制,例如,从干细胞发展到脂肪命运决定的前体脂肪细胞的机制。本文希望借助hASC成脂分化调控因子的研究发现新的成脂分化机制,为该方面机制弥补部分空白。近几年,随着高通量测序技术、染色质免疫共沉淀技术(Chromatin Immunoprecipitation,ChIP)的出现和成熟,针对控制发育、分化等的基因调控总网络的研究也快速成为基因组学以及表观遗传学的研究重点。本实验室创新发明了灵敏的表观遗传数据整合分析算法,该算法可以灵敏地识别不同ChIP-Seq数据中各类的富集信号模式下的局部富集信号,并且能够对不同长度维度的局部富集信号进行整合,从而构建具有生物学意义的复合富集信号以供分析。本文运用了表观遗传学研究方法并且结合了本实验室的创新算法,分析了hASC成脂分化过程的三个时间点的不同表观遗传学标记的ChIP-seq数据,例如,H3K4me3、H3K27me3、H3K27ace、H3K36me3等,基于染色体激活/抑制状态变化、转录因子作用区域变化等方面因素,挖掘出了基因组上一系列具有明显表观遗传学变化的编码或者非编码区域。最终,我们发现并证实了软骨寡聚基质蛋白(cartilage oligomeric matrix protein,COMP)影响着 hASC 成脂分化进程。另外,由于先前COMP基因只被报导与骨和软骨发育有着重大关系,因此本文中的发现将是对成脂分化机制以及COMP基因功能的全新开拓。
[Abstract]:Human adipose stem cells (HSCs) have attracted much attention since they were discovered and verified by Zuk PA in 2001. Compared with BM-MSCs derived from bone marrow, human adipose stem cells have a wide range of sources and are easy to obtain. Because of its high yield, it has rapidly become the focus of stem cell research and regenerative medicine. The process of adipogenic differentiation from adipose stem cells to adipocytes plays an important role in maintaining adipose tissue homeostasis, steady-state absorption of lipids and carbohydrates, and systemic metabolism. It is of great biological and biomedical significance to study the mechanism of adipogenic differentiation. However, except for the mechanisms related to the later stage of adipogenic differentiation, especially the mechanisms of early adipogenic differentiation, such as the development of stem cells to the preadipocytes determined by the fate of fat, are not well understood. In this paper, we hope to find a new mechanism of adipogenic differentiation with the help of the study of regulation factors of hASC adipogenic differentiation, and make up part of the blank for this mechanism. In recent years, with the development and maturity of chromatin immune coprecipitation (Chromatin immunoprecipitation ChIP) with high-throughput sequencing technology, the research on the total network of gene regulation for controlling development and differentiation has rapidly become the focus of genomics and epigenetics. The laboratory has invented a sensitive algorithm for the integration and analysis of epigenetic data. The algorithm can sensitively identify the local enrichment signals in various enrichment signal modes in different ChIP-Seq data. And the local enrichment signals of different length dimensions can be integrated to construct the biological complex enrichment signals for analysis. Using the method of epigenetics and the innovative algorithm of our laboratory, we analyzed the ChIP-seq data of different epigenetic markers at three time points in the process of adipogenic differentiation of hASC, such as H3K4me4me3m3m3m27me3H3K27aceer H3K36me3, etc. A series of coding or non-coding regions with apparent epigenetic changes were discovered based on the changes in the activation / inhibition status of chromosomes and the changes in the domain of transcription factors. Finally, we found that cartilage oligomeric matrix protein cartilage oligomeric matrix protein (omp) affected the process of hASC adipogenesis. In addition, since the previous COMP gene was only reported to be related to bone and cartilage development, the findings in this paper will be a new development of the mechanism of adipogenic differentiation and the function of COMP gene.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R329.2

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