Multi-omics functional analysis of non-coding regulatory genome for genomic medicine

摘要 不到2%的人类基因组序列是蛋白质编码基因。事实证明，至少 人类基因组中80%的非编码序列与某些染色质生化反应有关 修饰，超过70%的基因组DNA可以在不同阶段转录成RNA 在发展过程中。越来越多的证据表明，这些非编码调控序列是 对于空间和时间基因表达控制至关重要。然而，仍然难以确定 这些非编码调控DNA和RNA序列是否以及如何在各种生物学过程中发挥因果作用， 包括疾病在内的过程。特别是，增强子的活性如何精确地被 控制，以及非编码RNA如何招募效应蛋白来控制基因表达和基因组 功能，在很大程度上是未开发的。我的总体假设是，细胞整合效应蛋白和调节蛋白， 非编码DNA和RNA序列，以创建精确基因调控的功能谱 控制管理这些功能的规则可以通过定义关键组件来导出， 研究每一种功能是如何单独和组合的。为了测试这一点，我们开发了一个强大的， 创新的多组学方法，允许对分子组成进行全面分析 与非编码DNA和RNA序列相关。我的长期目标是开发一个预测性的， 对非编码基因组的功能性理解，这将阐明这些区域如何被 专门针对基因组医学。为了实现这一目标，我们寻求实现三个主要目标：1） 通过系统和靶向募集表观遗传效应子来控制增强子活性; 2）定义增强子的功能。 lncRNA介导的基因调控的调节组; 3）.开发创新的小鼠模型以研究功能 以及体内非编码基因组疾病模型的调节。我们的工作将产生广泛的影响， 基因组学研究和基因组学医学，开发新的方法和新的小鼠模型， 加深我们对非编码调控基因组的认识。

ABSTRACT Less than 2% of the human genome sequences are protein-coding genes. It has been shown that at least 80% of the non-coding sequences of human genome are associated with certain chromatin biochemical modifications, and more than 70% of the genomic DNA can be transcribed into RNAs at various stages during development. Accumulating evidence suggests that these non-coding regulatory sequences are critical for spatial and temporal gene expression control. However, it remains challenging to determine whether and how these non-coding regulatory DNA and RNA sequences play a causal in a variety biological processes including diseases. In particular, questions of how the activity of enhancers are precisely controlled, and how non-coding RNAs recruit effector proteins to control gene expression and genome function, are largely unexplored. My overall hypothesis is that, cells integrate effector proteins and regulatory non-coding DNA and RNA sequences to create a spectrum of functionalities for precise gene regulation control. The rules governing these functionalities can then be derived by defining the key components, and examining how each functions alone and in combination. To test this, we have developed a robust, innovative multi-omics approaches allowing for comprehensive analysis of the molecular composition associated with non-coding DNA and RNA sequences. My long-term goal is to develop a predictive and functional understanding of the non-coding genome, which will elucidate how these regions can be specifically targeted for genomic medicine. Toward this goal, we seek to achieve three major goals: 1) Control enhancer activity through systematic and targeted recruitment of epigenetic effectors; 2) Define the regulome of lncRNA-mediated gene regulation; 3). Develop innovative mouse model to study the function and regulation of non-coding genome disease model in vivo. Our work will have a broad impact to advance genomics research and genomics medicine by developing new approaches and new mouse models to deepen our knowledge on non-coding regulatory genome.