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.

项目概要 转座元件 (TE) 约占人类基因组的一半，以及一些 TE 亚家族 甚至可以包含数十万个副本，例如 LINE 和 SINE 元素。高度浓缩 TEs序列中的转录因子结合位点使TEs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 TE 逃脱了表观遗传沉默，并积极参与 宿主基因组的多种生物过程。 TEs 对脊椎动物长链的起源有重要贡献。 非编码RNA，一些TE也被发现在早期发育中发挥启动子的作用，一些 终末分化组织。我们最近的研究发现，驯化的啮齿动物特异性 TE 可以发挥作用 作为启动子启动小鼠组织中 300 多个基因的组织特异性转录 差异化。然而，人类基因组中驯化的TEs衍生启动子如何调节 不同组织和细胞类型中的基因转录尚不清楚。例如，我们不知道 有多少基因可以由 TE 衍生的启动子在特定的人体组织中转录；我们不知道 关于 TE 衍生启动子在同一组织的不同细胞类型中的使用；最后，如何 人类基因组中的驯化 TE 创造了保守蛋白的新的组织特异性表达模式 编码基因，仍然令人困惑。因此，在这个拟议的项目中，我们将重点研究组织和 细胞类型特异性基因转录由驯化的 TE 衍生启动子控制 人类基因组。利用大型联盟生成的大数据，例如 ENCODE、Roadmap 表观基因组学、GTEx 和人类细胞图谱，我们将对驯化的使用情况进行系统调查 人类基因组中源自 TE 的启动子。首先，我们将确定被驯化的 TE 人类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 通过使用我们建立的转录本，驯化 TE 衍生转录本的组织水平表达模式 组装管道来分析 ENCODE 和 GTEx 生成的组织批量 RNA-seq 数据。其次，我们 将研究驯化 TE 衍生转录物的细胞类型特异性表达模式，通过 使用新型生物信息学分析工具重建单细胞 RNA-seq 数据分析。最后，我们将 应用比较基因组学方法创建直系同源 TE 衍生蛋白的表达矩阵 跨多个物种的编码基因，并构建系统发育树来探索表达模式 TE 衍生的蛋白质编码基因在进化过程中的变化。