譜系形成過程中轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾的多組學(xué)整合分析
發(fā)布時(shí)間：2019-04-15 21:44
【摘要】：2003年,人類基因組計(jì)劃的完成標(biāo)志著生命科學(xué)進(jìn)入了新的里程碑,人們開啟了研究基因組序列的大門。近年來,隨著測序技術(shù)的發(fā)展,海量的高通量數(shù)據(jù)涌現(xiàn),包括ENCODE計(jì)劃,ROADMAP計(jì)劃,modENCODE計(jì)劃在內(nèi)的大型科學(xué)計(jì)劃應(yīng)運(yùn)而生,諸如基因表達(dá)量,DNA甲基化,組蛋白修飾,DNA高敏位點(diǎn)等測序數(shù)據(jù)為人們提供了廣泛的研究平臺(tái),但如何從這海量的數(shù)據(jù)中提取有用信息并作出生物學(xué)解釋仍是一個(gè)困擾著大家的科學(xué)問題。越來越多的研究表明,譜系形成早期,即植入前胚胎的發(fā)育過程經(jīng)歷了一系列劇烈的染色質(zhì)重編程事件,這種重編程現(xiàn)象不但介導(dǎo)了基因轉(zhuǎn)錄的重新啟動(dòng),同時(shí)塑造了胚胎干細(xì)胞的全能性,為之后的胚胎發(fā)育奠定了基礎(chǔ)。但重編程是如何進(jìn)行的,又有哪些因素發(fā)揮了重要作用?為了探討這一問題,我們討論了植入前胚胎發(fā)育過程中染色質(zhì)開放狀態(tài)的分布情況并分析了開放區(qū)間中轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾的變化規(guī)律,進(jìn)而對(duì)早期發(fā)育中細(xì)胞命運(yùn)的影響因素展開了猜想。在本研究中,我們首先分析了植入前胚胎發(fā)育中染色質(zhì)開放狀態(tài)的全基因組基本性質(zhì)以及其動(dòng)態(tài)變化規(guī)律,發(fā)現(xiàn),隨胚胎發(fā)育,越來越多的開放區(qū)域來自于基因組編碼區(qū)域,而且第一次細(xì)胞命運(yùn)決定時(shí)期ICM中染色質(zhì)性質(zhì)最為活躍,其開放區(qū)間長度最短且離基因轉(zhuǎn)錄起始位點(diǎn)最近。進(jìn)而,我們掃描并識(shí)別了開放區(qū)域中轉(zhuǎn)錄因子的結(jié)合位點(diǎn),由聚類分析發(fā)現(xiàn),開放區(qū)域中的轉(zhuǎn)錄因子表現(xiàn)出了發(fā)育階段的特異性。最后我們結(jié)合表觀遺傳的組蛋白修飾數(shù)據(jù)討論了發(fā)育過程中的組學(xué)信號(hào)變化情況,最終對(duì)細(xì)胞命運(yùn)的決定模型進(jìn)行了猜想。上述研究表明,在生命初期,轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾對(duì)胚胎植入前的重編程過程有著重要影響。我們接下來討論了胚胎植入后,轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾是如何影響胚胎干細(xì)胞分化為各類細(xì)胞并形成組織行駛功能的。雖然轉(zhuǎn)錄因子作為重要的蛋白分子,調(diào)控基因的表達(dá),但基因組中轉(zhuǎn)錄因子的結(jié)合位點(diǎn)僅為幾bp到十幾bp的小區(qū)間,然而,轉(zhuǎn)錄因子的結(jié)合位點(diǎn)卻呈現(xiàn)出了區(qū)域富集的現(xiàn)象,基因組中不到2%的區(qū)域富集了超過90%的轉(zhuǎn)錄因子結(jié)合位點(diǎn)。已有研究在果蠅、線蟲以及人類基因組中得到了這類轉(zhuǎn)錄因子高度富集的區(qū)間并定義為HOT region,如,通過22種轉(zhuǎn)錄因子的ChIP-seq數(shù)據(jù)在線蟲中發(fā)現(xiàn)了304個(gè)含有超過15種轉(zhuǎn)錄因子的HOT region。雖然這些轉(zhuǎn)錄因子高度的聚集在基因組較小的區(qū)間內(nèi),但它們是如何相互作用行駛功能的,又是如何影響人類疾病及癌癥的仍是一個(gè)未知的問題。為了探究這一問題,我們基于DHS數(shù)據(jù)開發(fā)了一種基因組HOT region的識(shí)別算法并在實(shí)驗(yàn)得到的HOT region中得到了驗(yàn)證,最終識(shí)別了154個(gè)代表性細(xì)胞系中的HOT region。進(jìn)而,我們從多方面刻畫了HOT region的發(fā)育分化相關(guān)功能并分析了胚胎干細(xì)胞到4個(gè)終端細(xì)胞的分化過程中HOT region及其表觀遺傳修飾的動(dòng)態(tài)變化規(guī)律。在識(shí)別并注釋了基因組熱點(diǎn)區(qū)域HOT region的基礎(chǔ)上,我們進(jìn)一步探究了HOT region與人類疾病及癌癥的關(guān)系。結(jié)合GWAS SNPs數(shù)據(jù),我們發(fā)現(xiàn),疾病及表型相關(guān)的變異位點(diǎn)傾向于在病理學(xué)相關(guān)的細(xì)胞及組織的HOT region中特異性富集;我們以造血細(xì)胞分化過程為例,詳細(xì)討論了疾病及表型的特異性變化規(guī)律,同時(shí),我們對(duì)幾種重要疾病及癌癥展開分析,進(jìn)一步說明了HOT region的重要意義。最后,我們探究了HOT region與部分致癌機(jī)理的關(guān)系,發(fā)現(xiàn),腫瘤的形成過程可能需要有腫瘤細(xì)胞特異的HOT region以調(diào)控相關(guān)致病基因的表達(dá)。為了探究譜系形成過程中,轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾發(fā)揮了怎樣的功能,我們首先基于已有數(shù)據(jù)分析了植入前胚胎發(fā)育過程中轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾的性質(zhì)和變化規(guī)律,進(jìn)而,我們識(shí)別并注釋了基因組中轉(zhuǎn)錄因子結(jié)合位點(diǎn)聚集的熱點(diǎn)區(qū)域,并分析了熱點(diǎn)區(qū)域及染色質(zhì)開放區(qū)間中轉(zhuǎn)錄因子調(diào)控和表觀遺傳修飾的性質(zhì)及變化規(guī)律,最后,我們討論了熱點(diǎn)區(qū)域與人類疾病及癌癥的關(guān)系。本研究著眼于細(xì)胞譜系的形成過程,重點(diǎn)關(guān)注于非編碼區(qū)域的調(diào)控功能,既為基因組非編碼區(qū)的研究增添了新的內(nèi)容,同時(shí)也對(duì)細(xì)胞命運(yùn)決定因素的展開了討論和思考。
[Abstract]:In 2003, the completion of the human genome project marked a new milestone in the life science, and people opened the door to the study of the genome sequence. In recent years, with the development of sequencing technology, massive high-throughput data has emerged, including the ENCODE program, the ROADMAP program, the modENCODE program, and so on, such as gene expression, DNA methylation, histone modification, Sequencing data, such as the DNA high-sensitivity site, provides a wide range of research platforms, but how to extract useful information from this mass of data and to make a biological explanation remains a scientific problem. more and more studies have shown that the early stage of the genealogy, i. e. the development of pre-implantation embryos, has experienced a series of severe chromatin reprogramming events that not only mediate the restart of the gene transcription, but also shape the potency of the embryonic stem cells, And laid the foundation for the development of the later embryo. But what are the factors that play an important role in re-programming? In order to study this problem, we discussed the distribution of the open state of chromatin in the process of pre-implantation embryo development and analyzed the regulation of transcription factor and the change of epigenetic modification in the open interval, and then on the influence factors of the cell fate in the early development. In this study, we first analyzed the basic properties of the whole genome and its dynamic changes in the open state of the chromatin in the pre-implantation embryo development, and found that, with the development of the embryo, more and more open regions come from the genome coding region, In the first time, the chromatin in the ICM was most active, and its open interval was the shortest and closest to the gene transcription initiation site. In addition, we scan and identify the binding sites of transcription factors in the open region, and it is found by cluster analysis that the transcription factor in the open region shows the specificity of the development stage. In the end, we discuss the change of the metabonomics signal in the development process with the epigenetic histone modification data, and finally the decision model of the cell fate is made. The above-mentioned studies have shown that the regulation of transcription factors and epigenetic modification in the early stage of life have an important effect on the reprogramming of the pre-implantation of the embryo. After we discussed the implantation of the embryo, the regulation and epigenetic modification of the transcription factor affects the differentiation of the embryonic stem cells into various cells and forms the function of the driving of the tissue. Although the transcription factor serves as an important protein molecule, the expression of the gene is regulated, but the binding site of the transcription factor in the genome is only a few bp to a few bp small intervals, Less than 2% of the region in the genome is enriched with more than 90% of the transcription factor binding site. There have been studies in Drosophila, Nematode and the human genome that are highly enriched in this type of transcription factor and are defined as HOT regions, such as the discovery of 304 HOT regions containing more than 15 transcription factors in the Nematode via the ChIP-seq data of 22 transcription factors. Although these transcription factors are highly concentrated in smaller sections of the genome, how they interact with the driving function and how they affect human diseases and cancer remains an unknown problem. In order to explore this problem, we developed a genome HOT region recognition algorithm based on the DHS data and verified the HOT region obtained in the experiment, and finally identified the HOT region in 154 representative cell lines. In addition, we describe the development and differentiation-related function of the HOT region from many aspects and analyze the dynamic changes of the HOT region and its epigenetic modification in the differentiation of the embryonic stem cells to the four terminal cells. On the basis of identifying and annotating the HOT region of the genome, we further explore the relationship between the HOT region and the human disease and the cancer. In combination with the data of the GWAS SNPs, we found that the disease and phenotype-related mutation sites tend to be specific in the HOT region of the pathology-related cells and tissues; we take the hematopoietic cell differentiation process as an example to discuss the specific changes of the disease and phenotype in detail, and at the same time, We analyze several important diseases and cancer, and further illustrate the significance of the HOT region. Finally, we explore the relationship between the HOT region and some of the carcinogenic mechanism, and it is found that the formation process of the tumor may need the specific HOT region of the tumor cell to regulate the expression of the related pathogenic gene. in ord to explore that function of transcription factor regulation and epigenetic modification in the course of the formation of the genealogy, we first analyze the nature and the change rule of transcription factor regulation and epigenetic modification in the process of pre-implantation embryo development based on the existing data analysis, and then, We identified and noted the hot spot region of the transcription factor binding site in the genome, and analyzed the property and the change rule of the transcription factor regulation and epigenetic modification in the hot spot region and the chromatin opening region, and finally, We discussed the relationship between hot spots and human diseases and cancer. This study focuses on the formation of the cell lineage, and focuses on the regulatory function of the non-coding region, which has added new contents to the study of the non-coding region of the genome, and also discussed and thought on the determinants of the cell fate.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：Q75
本文編號(hào)：2458520
[Abstract]:In 2003, the completion of the human genome project marked a new milestone in the life science, and people opened the door to the study of the genome sequence. In recent years, with the development of sequencing technology, massive high-throughput data has emerged, including the ENCODE program, the ROADMAP program, the modENCODE program, and so on, such as gene expression, DNA methylation, histone modification, Sequencing data, such as the DNA high-sensitivity site, provides a wide range of research platforms, but how to extract useful information from this mass of data and to make a biological explanation remains a scientific problem. more and more studies have shown that the early stage of the genealogy, i. e. the development of pre-implantation embryos, has experienced a series of severe chromatin reprogramming events that not only mediate the restart of the gene transcription, but also shape the potency of the embryonic stem cells, And laid the foundation for the development of the later embryo. But what are the factors that play an important role in re-programming? In order to study this problem, we discussed the distribution of the open state of chromatin in the process of pre-implantation embryo development and analyzed the regulation of transcription factor and the change of epigenetic modification in the open interval, and then on the influence factors of the cell fate in the early development. In this study, we first analyzed the basic properties of the whole genome and its dynamic changes in the open state of the chromatin in the pre-implantation embryo development, and found that, with the development of the embryo, more and more open regions come from the genome coding region, In the first time, the chromatin in the ICM was most active, and its open interval was the shortest and closest to the gene transcription initiation site. In addition, we scan and identify the binding sites of transcription factors in the open region, and it is found by cluster analysis that the transcription factor in the open region shows the specificity of the development stage. In the end, we discuss the change of the metabonomics signal in the development process with the epigenetic histone modification data, and finally the decision model of the cell fate is made. The above-mentioned studies have shown that the regulation of transcription factors and epigenetic modification in the early stage of life have an important effect on the reprogramming of the pre-implantation of the embryo. After we discussed the implantation of the embryo, the regulation and epigenetic modification of the transcription factor affects the differentiation of the embryonic stem cells into various cells and forms the function of the driving of the tissue. Although the transcription factor serves as an important protein molecule, the expression of the gene is regulated, but the binding site of the transcription factor in the genome is only a few bp to a few bp small intervals, Less than 2% of the region in the genome is enriched with more than 90% of the transcription factor binding site. There have been studies in Drosophila, Nematode and the human genome that are highly enriched in this type of transcription factor and are defined as HOT regions, such as the discovery of 304 HOT regions containing more than 15 transcription factors in the Nematode via the ChIP-seq data of 22 transcription factors. Although these transcription factors are highly concentrated in smaller sections of the genome, how they interact with the driving function and how they affect human diseases and cancer remains an unknown problem. In order to explore this problem, we developed a genome HOT region recognition algorithm based on the DHS data and verified the HOT region obtained in the experiment, and finally identified the HOT region in 154 representative cell lines. In addition, we describe the development and differentiation-related function of the HOT region from many aspects and analyze the dynamic changes of the HOT region and its epigenetic modification in the differentiation of the embryonic stem cells to the four terminal cells. On the basis of identifying and annotating the HOT region of the genome, we further explore the relationship between the HOT region and the human disease and the cancer. In combination with the data of the GWAS SNPs, we found that the disease and phenotype-related mutation sites tend to be specific in the HOT region of the pathology-related cells and tissues; we take the hematopoietic cell differentiation process as an example to discuss the specific changes of the disease and phenotype in detail, and at the same time, We analyze several important diseases and cancer, and further illustrate the significance of the HOT region. Finally, we explore the relationship between the HOT region and some of the carcinogenic mechanism, and it is found that the formation process of the tumor may need the specific HOT region of the tumor cell to regulate the expression of the related pathogenic gene. in ord to explore that function of transcription factor regulation and epigenetic modification in the course of the formation of the genealogy, we first analyze the nature and the change rule of transcription factor regulation and epigenetic modification in the process of pre-implantation embryo development based on the existing data analysis, and then, We identified and noted the hot spot region of the transcription factor binding site in the genome, and analyzed the property and the change rule of the transcription factor regulation and epigenetic modification in the hot spot region and the chromatin opening region, and finally, We discussed the relationship between hot spots and human diseases and cancer. This study focuses on the formation of the cell lineage, and focuses on the regulatory function of the non-coding region, which has added new contents to the study of the non-coding region of the genome, and also discussed and thought on the determinants of the cell fate.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：Q75
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 Hongzhu Qu;Xiangdong Fang;;A Brief Review on the Human Encyclopedia of DNA Elements (ENCODE) Project[J];Genomics, Proteomics & Bioinformatics;2013年03期
，本文編號(hào)：2458520
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