Transcriptional regulation of domesticated transposable elements-derived promoters in human genome

人类基因组中驯化转座元件衍生启动子的转录调控

• 批准号: 10452608
• 负责人: Bo Zhang
• 金额: $ 37.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452608
• 关键词: Atlases; Behavior; Big Data; Binding Sites; Bioinformatics; Biological Process; Cells; Code; DNA Transposable Elements; Data; Data Analyses; Development; Elements; Evolution; Genes; Genetic Transcription; Genome; Genomic approach; Genotype-Tissue Expression Project; Human; Human Genome; Mus; Pattern; Phylogenetic Analysis; Play; Proteins; Rodent; Role; Short Interspersed Nucleotide Elements; Surveys; Tissue Differentiation; Tissues; Transcript; Transcriptional Regulation; Trees; Untranslated RNA; cell type; comparative genomics; epigenetic silencing; epigenomics; human tissue; improved; novel; promoter; single-cell RNA sequencing; tool; transcription factor; transcriptome sequencing

Project Summary Transposable elements (TEs) comprise roughly half of the human genomes, and some TE subfamilies can even contain hundreds of thousands of copies, such as LINE and SINE elements. Highly enriched transcriptional factor binding sites in the TEs sequence enable TEs the huge regulatory potential to the host genome. Mounting evidence suggests some of TEs escaped from epigenetic silencing and actively involved in multiple biological processes of host genome. TEs are significant contributors to the origin of vertebrate long non-coding RNAs, and some TEs are also found to play roles as promoters in early development and some terminally differentiated tissues. Our recent study found that domesticated rodent-specific TEs can play roles as promoters to initiate the tissue-specific transcription of more than 300 genes during mouse tissue differentiation. However, how the domesticated TEs-derived promoters in the human genome to regulate the gene transcription in distinct tissues and cell types, is not clearly characterized. For example, we do not know how many genes can be transcribed by TEs-derived promoters in particular human tissues; we have no idea about the usage of TEs-derived promoters in the different cell types from the same tissue; finally, how domesticated TEs in the human genome created novel tissue-specific expression pattern of conserved protein- coding genes, is still mystified. Thus, in this proposed project, we will focus on investigating the tissue- and cell type-specific gene transcription controlled by the domesticated TEs-derived promoters in the human genome. Leveraging the big data generated by large consortiums, e.g., ENCODE, Roadmap Epigenomics, GTEx, and Human Cell Atlas, we will perform a systematic survey of the usage of domesticated TEs-derived promoters in the human genome. Firstly, we will identify the TEs that were domesticated as promoters of protein-coding genes and non-coding genes in the human genome, and further characterize the tissue-level expression pattern of domesticated TEs-derived transcripts, by using our established transcripts assemble pipeline to analyze the tissue bulk RNA-seq data generated by ENCODE and GTEx. Secondly, we will investigate the cell-type-specific expression pattern of domesticated TEs-derived transcripts, by reconstructing the single-cell RNA-seq data analysis with novel bioinformatics analysis tool. Finally, we will apply comparative-genomics approaches to create the expression matrix of orthologous TEs-derived protein- coding genes across multi-species, and construct the phylogenetic trees to explore the expression pattern changes of TEs-derived protein-coding genes during evolution.

项目摘要 转座因子（Transposable elements，TE）约占人类基因组的一半， 甚至可以包含数十万个副本，例如LINE和SINE元素。高浓缩 TE序列中的转录因子结合位点使TE对宿主具有巨大的调节潜力 基因组越来越多的证据表明，一些TEs逃脱了表观遗传沉默，并积极参与了 宿主基因组的多种生物学过程。TE是脊椎动物长链起源的重要贡献者。 非编码RNA和一些TE也被发现在早期发育中起启动子的作用， 终末分化组织我们最近的研究发现，家养啮齿动物特有的TE可以发挥作用， 作为启动子，在小鼠组织中启动300多个基因的组织特异性转录， 分化然而，人类基因组中驯化的TES衍生的启动子如何调控基因表达， 在不同组织和细胞类型中的基因转录没有明确的特征。例如，我们不知道 在特定的人体组织中，有多少基因可以被TEs衍生的启动子转录;我们不知道 关于TES衍生的启动子在来自相同组织的不同细胞类型中的使用;最后，如何 人类基因组中驯化的TE创造了保守蛋白质的新组织特异性表达模式， 编码基因仍然是个谜因此，在这个拟议的项目中，我们将重点研究组织- 细胞类型特异性基因转录控制的驯化TES衍生的启动子在 人类基因组利用大型财团产生的大数据，ENCODE，路线图 表观基因组学，GTEx和人类细胞图谱，我们将进行一个系统的调查使用驯化的 人类基因组中的TES衍生启动子。首先，我们将确定被驯化为 人基因组中蛋白质编码基因和非编码基因的启动子，并进一步表征了 通过使用我们建立的转录本，驯化的TEs衍生转录本的组织水平表达模式 组装流水线分析ENCODE和GTEx生成的组织批量RNA-seq数据。其次我们 将调查细胞类型特异性表达模式的驯化TES衍生的转录本， 用新的生物信息学分析工具重构单细胞RNA-seq数据分析。最后我们将 应用比较基因组学方法来创建直链淀粉衍生蛋白的表达矩阵- 编码基因，并构建系统发育树，探索表达模式 TEs衍生蛋白编码基因在进化过程中的变化。