Characterizing the comprehensive gene regulatory basis of autoimmunity.

项目摘要 增强子是基本的基因调控元件，在发育和疾病中发挥关键作用，但 关于增强剂本身是如何受到监管的，人们知之甚少。上游的基因途径是什么 对激活增强剂很重要吗？哪些蛋白质与增强子结合并调节近端基因 表情？这些调控因素如何影响复杂的表型？虽然大规模的努力，如 DNA元素百科全书(ENCODE)联盟在制定纲要方面取得了可喜的进展 对于增强剂，我们缺乏必要的工具来理解增强子调控，更广泛地说，它在 疾病。 为了解决这一关键缺陷，我将首先开发一种新的、高通量的方法--一种大规模 平行报告分析或TransMPRA--可以解决目前识别蛋白质调节的局限性 以可伸缩的方式进行元素交互。然后，我将应用TransMPRA以及其他高吞吐量 基因组学分析和多模式数据分析，以揭示全面的基因调控基础 自身免疫力。我期待这一新方法，加上它最初应用的结果，将会有广泛的应用。 对理解基因调控在包括人类自身免疫在内的复杂性状中的作用的启示 精神错乱。 除了我的研究计划外，我还将接受一项奖学金培训计划，该计划将继续完善我的技能，如 他是科学界的研究员和积极贡献者。拟议的研究和研究员培训 计划将在我的赞助商和共同赞助商Jay Shendure博士和Cole TRapnell博士的实验室进行， 华盛顿大学基因组科学系。我特别选择了我的顾问和机构 因为他们在进行尖端研究和培训方面有着出色的记录 一代科学思想领袖。

Project Summary Enhancers are fundamental gene regulatory elements with critical roles in development and disease, and yet relatively little is known about how enhancers themselves are regulated. What are the upstream gene pathways important for activating enhancers? Which proteins bind to an enhancer and modulate proximal gene expression? How do these regulatory factors affect complex phenotypes? While large-scale efforts such as the Encyclopedia of DNA Elements (ENCODE) Consortium have made laudable progress towards a compendium of enhancers, we lack the tools necessary to understand enhancer regulation, and more broadly, its role in disease. To address this critical shortcoming, I will first develop a new, high-throughput method — a trans massively parallel reporter assay or transMPRA — that can address current limitations of identifying protein-regulatory element interactions in a scalable manner. I will then apply transMPRA, along with other high-throughput genomics assays and multimodal data analysis, to reveal the comprehensive gene-regulatory basis of autoimmunity. I anticipate that this new method together with findings from its initial application will have broad implications toward understanding the role of gene regulation in complex traits including human autoimmune disorders. In addition to my research proposal, I will undergo a fellowship training plan that continues to refine my skills as a researcher and active contributor to the science community. The proposed research and fellowship training plan will take place in the labs of my sponsor and co-sponsor, Dr. Jay Shendure and Dr. Cole Trapnell, in the Department of Genome Sciences at University of Washington. I specifically chose my advisors and institution because they have an outstanding track record of performing cutting edge research and training the next generation of science thought leaders.