本文關(guān)鍵詞：非編碼RNA在人類癌癥中的轉(zhuǎn)錄調(diào)控研究　出處：《華東師范大學(xué)》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 癌癥 非編碼RNA miRNA lncRNA 轉(zhuǎn)錄因子 ceRNA 癌癥轉(zhuǎn)移 數(shù)據(jù)庫(kù)

【摘要】：癌癥是威脅人類生命健康最嚴(yán)重的疾病之一,其發(fā)病率與死亡率一直處于各種疾病之首。目前已發(fā)現(xiàn)的癌癥類型有100多種。有研究表明,非編碼RNA,如小RNA(miRNA),長(zhǎng)鏈非編碼RNA(lncRNA)在癌癥的發(fā)生發(fā)展過(guò)程中發(fā)揮著重要的調(diào)控作用。因此,對(duì)癌癥中非編碼RNA的轉(zhuǎn)錄調(diào)控研究是了解、治療癌癥的重要手段。近些年來(lái),非編碼RNA在癌癥中的研究方法還非常有限。生物信息學(xué)算法和高通量測(cè)序技術(shù)的發(fā)展為癌癥中非編碼RNA的轉(zhuǎn)錄調(diào)控研究提供了新的理論和方法,同時(shí),若干與癌癥轉(zhuǎn)錄調(diào)控相關(guān)的科學(xué)問(wèn)題也需要更全面的審視和探討。本論文所關(guān)注的重點(diǎn)是miRNA和lncRNA在癌癥中轉(zhuǎn)錄調(diào)控功能的研究。本論文的第一部分是miRNA與轉(zhuǎn)錄因子聯(lián)合調(diào)控作用在多種癌癥和正常組織細(xì)胞系中的研究。首先,我們研究了 19種人類細(xì)胞系中基因是否受miRNA靶向調(diào)控同基因轉(zhuǎn)錄因子結(jié)合位點(diǎn)數(shù)目之間的關(guān)系。研究結(jié)果不僅進(jìn)一步支持了miRNA偏向于結(jié)合轉(zhuǎn)錄調(diào)控復(fù)雜的基因,同時(shí)還發(fā)現(xiàn)癌癥和正常組織細(xì)胞系具有類似的調(diào)控機(jī)制。因此,miRNA和轉(zhuǎn)錄因子的這種聯(lián)合調(diào)控作用具有普遍的意義。通過(guò)對(duì)轉(zhuǎn)錄因子結(jié)合位點(diǎn)的位置特征進(jìn)行分析研究,我們發(fā)現(xiàn)基因是否受miRNA調(diào)控主要受基因轉(zhuǎn)錄起始區(qū)域的轉(zhuǎn)錄因子結(jié)合位點(diǎn)信息影響。在此基礎(chǔ)上,我們構(gòu)建了數(shù)學(xué)模型,成功利用基因轉(zhuǎn)錄因子結(jié)合位點(diǎn)信息對(duì)基因是否受miRNA調(diào)控進(jìn)行準(zhǔn)確預(yù)測(cè)。通過(guò)對(duì)單個(gè)miRNA的靶基因進(jìn)行預(yù)測(cè)研究,我們發(fā)現(xiàn),miRNA和轉(zhuǎn)錄因子的這種聯(lián)合調(diào)控作用可以為優(yōu)化miRNA靶基因識(shí)別算法提供新的思路。本論文的第二部分是lncRNA-mRNA類型的競(jìng)爭(zhēng)性內(nèi)源RNA(ceRNA)調(diào)控網(wǎng)絡(luò)在癌癥和癌旁組織中的比較研究。首先我們對(duì)13種癌癥類型的癌癥和癌旁組織分別構(gòu)建了 ceRNA調(diào)控網(wǎng)絡(luò)。通過(guò)對(duì)同種癌癥類型中癌癥和癌旁組織進(jìn)行網(wǎng)絡(luò)比較分析,我們發(fā)現(xiàn)癌旁組織擁有更多的ceRNA調(diào)控作用,而癌變過(guò)程中僅有少部分ceRNA調(diào)控作用得到了保留。通過(guò)對(duì)癌變過(guò)程中增加或消失的ceRNA調(diào)控作用進(jìn)行功能分析,我們發(fā)現(xiàn),增加的ceRNA調(diào)控作用往往會(huì)帶來(lái)細(xì)胞周期的波動(dòng),而消失的ceRNA調(diào)控作用則會(huì)對(duì)Wnt信號(hào)通路和細(xì)胞凋亡信號(hào)通路產(chǎn)生影響。本論文的第三部分是構(gòu)建人類癌癥轉(zhuǎn)移數(shù)據(jù)庫(kù)(HCMDB)。首先,我們基于已發(fā)表的文獻(xiàn),對(duì)miRNA、lncRNA以及蛋白編碼基因在癌癥轉(zhuǎn)移過(guò)程中發(fā)揮的功能進(jìn)行了人工整理,共篩選出2183個(gè)與癌癥轉(zhuǎn)移相關(guān)的基因,包括1901個(gè)蛋白編碼基因,24個(gè)lncRNA基因和203個(gè)miRNA。然后,我們從GEO和TCGA數(shù)據(jù)庫(kù)中搜集了 152套與癌癥轉(zhuǎn)移相關(guān)的表達(dá)數(shù)據(jù),通過(guò)更合理的樣品分組設(shè)計(jì),對(duì)癌癥轉(zhuǎn)移相關(guān)的基因進(jìn)行了鑒定和調(diào)控網(wǎng)絡(luò)分析。該研究基于文獻(xiàn)信息和高通量數(shù)據(jù)挖掘,構(gòu)建了第一個(gè)癌癥轉(zhuǎn)移相關(guān)的基因表達(dá)和功能數(shù)據(jù)庫(kù),為接下來(lái)探索癌癥轉(zhuǎn)移過(guò)程中非編碼RNA和蛋白編碼基因的功能提供了數(shù)據(jù)支持�？傊�,本論文基于大量公共的轉(zhuǎn)錄組和表觀遺傳學(xué)數(shù)據(jù),系統(tǒng)地研究了若干癌癥中非編碼RNA參與的轉(zhuǎn)錄調(diào)控機(jī)制,構(gòu)建了與癌癥轉(zhuǎn)移相關(guān)的基因表達(dá)和功能數(shù)據(jù)庫(kù)。這對(duì)于未來(lái)癌癥中非編碼RNA的研究可能具有重要的意義,而且為今后的癌癥轉(zhuǎn)錄調(diào)控研究提供有意義的思路和數(shù)據(jù)挖掘平臺(tái)。
[Abstract]:Cancer is one of the most serious disease threat to human life and health, its incidence and mortality have been in all kinds of diseases. It has been found that the type of cancer. There are 100 kinds of studies have shown that non RNA encoding, such as RNA (miRNA), a long chain of non encoding RNA (lncRNA) plays an important role in the regulation of in the process of tumorigenesis. Therefore, study on the transcriptional regulation of non encoding RNA in cancer is an important means of understanding, for the treatment of cancer. In recent years, the research method of non encoding of RNA in cancer is still very limited. The development of bioinformatics algorithms and high-throughput sequencing technology provides a new theory and method. To study the transcriptional regulation of non encoding RNA in cancer at the same time, some associated with cancer transcriptional regulation of scientific problems requires a more comprehensive review and discussion. The focus of this paper is concerned with the miRNA and lncRNA in cancer control function transfer record Study. The first part of this paper is to study the miRNA and transcription factor combined with regulatory role in cell lines of many types of cancer and normal tissues. Firstly, we studied 19 genes in human cell lines by miRNA targeting the same gene transcription factor binding sites. The relationship between the number of research results not only further support miRNA combined with the bias in the complex transcriptional regulation genes, it was also found that the cancer and normal tissue cells have a similar mechanism of regulation. Therefore, it has universal significance and the role of miRNA and regulation of transcription factors. The transcription factor binding site location characteristics analysis, we found that the gene is mainly regulated by transcription by miRNA gene transcription initiation region binding site information. On this basis, we established the mathematical model, the successful use of gene transcription factor binding Site information on whether the gene regulated by miRNA. Through the accurate prediction of single miRNA of target gene prediction research, we found that the combined effect of miRNA and the regulation of transcription factors can provide a new idea for the optimization of miRNA target gene identification algorithm. The second part of this thesis is the competition of endogenous RNA type lncRNA-mRNA (ceRNA) Comparative Study on the regulation of network organization in cancer and para cancer. First we on the 13 types of cancer and cancer adjacent tissues were constructed by ceRNA regulation network. Through a network of the same type of cancer in cancer and paracancerous tissues of comparative analysis, we found that the adjacent tissues have ceRNA more regulatory role, and carcinogenesis just a few of ceRNA regulation have been retained. Through the functional analysis, the regulatory role of ceRNA increased or disappeared during the carcinogenesis process we found that increased CE RNA regulation often leads to cell cycle fluctuations, ceRNA regulation will disappear and effect on Wnt signaling pathway and apoptosis signal pathway. The third part of this thesis is to build a database of human cancer metastasis (HCMDB). First, we have published literature, based on miRNA, lncRNA and protein encoding play in the process of cancer metastasis gene function in the manual sorting, we screened 2183 genes associated with cancer metastasis, including 1901 protein encoding genes, 24 lncRNA genes and 203 miRNA. then, we collected 152 sets of cancer metastasis and expression of related data from GEO and TCGA database, through the sample group the design is more reasonable, the cancer metastasis related genes were identified and regulatory networks. The study of literature information and high-throughput data mining based on the construction of the first cancer metastasis The gene expression and function of the database, provides data support for the next exploration of the non protein encoding gene encoding RNA and cancer metastasis in the process of function. In short, this paper based on a large number of public transcriptome and epigenetic data, systematically studied the mechanism of transcriptional regulation of non coding RNA in several cancers, construct gene expression the function and database related with cancer metastasis. For the future research on non RNA encoding in cancer may have important significance, but also provide meaningful ideas and data mining platform for the study of transcriptional regulation of cancer in the future.

【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R730.2

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