Connecting transposable elements and regulatory innovation using ENCODE data

使用 ENCODE 数据连接转座元件和监管创新

• 批准号: 10241106
• 负责人: Barak A Cohen
• 金额: $ 46.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241106
• 关键词: 3-Dimensional; Address; Anatomy; Biological Process; Cells; Communication; Computing Methodologies; DNA; DNA Sequence; DNA Transposable Elements; Data; Development; Disease; Elements; Epigenetic Process; Evolution; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Health; Human; Human Activities; Human Genome; Link; Location; Malignant Neoplasms; Mammals; Methodology; Methods; Modeling; Modification; Mus; Nature; Paste substance; Play; Property; Regulation; Regulator Genes; Regulatory Element; Research Personnel; Role; Shapes; Statistical Methods; Statistical Models; Tissues; Untranslated RNA; Variant; algorithmic methodologies; cancer cell; innovation; novel; web portal

PROJECT SUMMARY Repetitive transposable elements (TEs) comprise over 50% of the human genome. While some investigators regard TEs as “parasitic” DNA, other studies suggest that TEs play a more constructive role in genome evolution by providing raw material for new biological functions. For example, TEs commonly harbor active cis-regulatory elements that are occasionally co-opted during evolution to wire new gene regulatory networks. While investigators now recognize the importance of TEs in gene regulation, TEs remain under-analyzed in high-throughput data because of methodological hurdles associated with their repetitive nature. Thus, the impact of TEs on the regulation of the human genome, both in normal development and disease, remains largely uncharacterized. We propose to develop novel computational methods to assess and clarify the impact of TEs in regulatory innovation using ENCODE data. In Specific Aim 1 we will develop new algorithms and statistical methods to predict active regulatory elements encoded by TEs from heterogeneous ENCODE data. If successful, we will generate a profile of TE-derived regulatory elements and their predicted targets across diverse cell/tissue types and developmental stages, revealing new gene regulatory networks wired by TEs. With these new methods we also intend to examine the extent of TE dysregulation in cancer cells and its transcriptional consequences. In Specific Aim 2 we will extend the models developed in Aim 1 to understand the role of TEs in shaping the 3D topology of the genome, which is intimately connected to genome function. We will investigate the role of TEs in partitioning the genome into chromosomal domains that orchestrate communication between cis-regulatory elements and their target genes. In particular, we will quantify the extent to which TEs drive conservation and divergence in genome topology across mammal species. In Specific Aim 3 we will take advantage of the repetitive nature of TEs to develop a novel statistical model that links sequence changes in different copies of TEs to epigenetic and functional differences. The numerous, but slightly different copies of a TE present in a single genome provide a unique opportunity to identify sequence variants that underlie epigenetic modification, which will further our understanding of how TEs become co-opted for host gene regulation. Finally, in Specific Aim 4, we will deploy our recently developed Repeat Element Browser as a web portal and downloadable application specifically tailored for investigators to analyze, visualize and explore data produced by ENCODE, others, and their own data in the context of TEs. The methods developed in this proposal will have a high impact on the utility of the data produced by ENCODE and will greatly expand our understanding of the contribution of TEs to non-coding regulatory elements in healthy tissues and disease.

项目总结 重复转座元件(TES)占人类基因组的50%以上。虽然有些人 研究人员认为TES是寄生的DNA，其他研究表明TES在疾病中发挥更具建设性的作用 通过为新的生物功能提供原料来实现基因组进化。例如，工商业污水附加费通常 含有活性的顺式调控元件，在进化过程中偶尔被增选来连接新的基因 监管网络。虽然研究人员现在认识到TES在基因调控中的重要性，但TES 在高通量数据中仍然分析不足，因为与其相关的方法障碍 重复性。因此，TES对人类基因组调控的影响，在正常情况下 发展和疾病，在很大程度上仍然没有特征。我们建议开发新的计算 方法使用ENCODE数据评估和澄清TES在监管创新中的影响。在……里面 具体目标1我们将开发新的算法和统计方法来预测活跃的调控成分 由来自异类ENCODE数据的TES编码。如果成功，我们将生成TE派生的配置文件 不同细胞/组织类型和发育阶段的调控元件及其预测靶点， 揭示了由TES连接的新的基因调控网络。通过这些新的方法，我们还打算检查 癌细胞中TE失调的程度及其转录后果。在具体目标2中，我们 我将扩展在目标1中开发的模型，以了解TES在塑造 基因组，这与基因组的功能密切相关。我们将研究TES在分区中的作用 基因组进入染色体区域，协调顺式调控元件之间的通信 以及它们的目标基因。特别是，我们将量化工商业污水附加费推动保护和 哺乳动物物种间基因组拓扑学上的差异。在具体目标3中，我们将利用 TES的重复性，以开发一种新的统计模型，将不同拷贝中的序列变化联系起来 TES的表观遗传和功能差异。TE礼物的众多但略有不同的副本 为识别构成表观遗传学基础的序列变异提供了独特的机会 修饰，这将加深我们对TES如何被增选用于宿主基因调控的理解。 最后，在特定的目标4中，我们将部署我们最近开发的Repeat Element浏览器作为Web门户 以及专门为调查人员量身定做的可下载应用程序，用于分析、可视化和探索数据 由ENCODE、其他公司和他们自己的数据在TES的背景下产生。在本课程中开发的方法 这项提议将对ENCODE产生的数据的效用产生很大影响，并将极大地扩大我们的 了解TES对健康组织和疾病中非编码调控元件的贡献。