Connecting transposable elements and regulatory innovation using ENCODE data

项目摘要 重复转座因子（TE）占人类基因组的50%以上。虽然一些 研究人员认为TE是“寄生的”DNA，其他研究表明，TE在 基因组进化提供了新的生物功能的原料。例如，TE通常 在进化过程中偶尔会被吸收，以连接新的基因 监管网络。虽然研究人员现在认识到TE在基因调控中的重要性， 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，TE对人类基因组调控的影响，无论是在正常的 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 使用ENCODE数据评估和澄清TE在监管创新中的影响的方法。在 具体目标1我们将开发新的算法和统计方法来预测活性调控元件 由来自异构ENCODE数据的TE编码。如果成功，我们将生成TE衍生的 调节元件及其在不同细胞/组织类型和发育阶段的预测靶标， 揭示了由TEs连接的新基因调控网络。通过这些新方法，我们还打算检查 癌细胞中TE失调的程度及其转录后果。具体目标2 将扩展目标1中开发的模型，以了解TE在塑造三维拓扑结构中的作用。 基因组，这是密切相关的基因组功能。我们将研究TE在分区中的作用 将基因组转化为染色体结构域，协调顺式调节元件之间的通讯 和它们的靶基因。特别是，我们将量化TE推动保护的程度， 哺乳动物物种间基因组拓扑结构的差异。在具体目标3中，我们将利用 TE的重复性质，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 与表观遗传和功能差异的关系。存在的TE的许多但略有不同的副本 在单个基因组中提供了鉴定作为表观遗传基础序列变异的独特机会 修饰，这将进一步我们了解如何成为增选的TE宿主基因调控。 最后，在SpecificAim 4中，我们将部署我们最近开发的RepeatElementBrowser作为Web门户 和可下载的应用程序，专为研究人员分析，可视化和探索数据而设计 由ENCODE、其他人和他们自己的数据在TE的背景下产生。在此开发的方法 该提案将对ENCODE产生的数据的实用性产生很大影响，并将大大扩展我们的 了解TE对健康组织和疾病中非编码调控元件的贡献。

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.