Center for Genomic Editing and Recording: Development and Application of Next-Generation Genome and Epigenome Editing Methods to Advance the Study and Treatment of Human Disease

基因组编辑和记录中心：项目总结 DNA测序和生物信息学的最新进展产生了大量的序列变体 与疾病相关的，原则上，这些疾病掌握着预防医学和 治疗性干预。然而，实现个性化医疗的前景将需要准确的 DNA序列和基因表达的操纵以及功能后果的询问 以目前不可能达到的规模和准确度对序列变体进行分析。 基因组编辑和记录中心(CGER)将通过创建 检测、改变和记录单个细胞和组织中基因组序列和输出的技术。 CGER将利用CRISPR-Cas蛋白的可编程DNA结合和尼克酶活性以及 设计了锌指和TALL蛋白，创造了新一代工具来精确设计基因组 和表观基因组。这些平台将使核和线粒体的高精度工程成为可能 基因组以及信使RNA、长非编码RNA和许多 其他监管元素，如增强剂和绝缘体区域。关键的是，这些改变是可以进行的 而不会给DNA引入双链断裂，从而避免DNA毒性并将对 复杂且难以控制的内源性DNA修复途径。总的来说，这些技术将迎来 更安全、高精度和多元化的基因组和表观基因组编辑的新时代。 此外，我们还将利用这些平台开发更高级别的多通道分子记录器， 将使我们能够在活体环境中跟踪和重建细胞的生命历史。我们将增加跟随的能力 细胞在空间和时间上以及记录它们过去的细胞状态的历史到现有的系统发育 血统追踪系统在这个中心的前身中首创。 该中心将由一个团队领导，他们共同拥有开发大胆、 具有影响力的新工具，以扩展其精度、有效性、安全性和范围，并最终利用这些新工具 开发探索基本生物学和生物医学问题的新策略的能力。我们的 多学科团队有着丰富的合作历史，这在CEGS的推动下得到了极大的推动 结构，如果每个共同PI一直在处理类似的问题 与世隔绝。利用怀特黑德研究所、麻省理工学院、布罗德研究所、哈佛大学、 哈佛医学院、普林斯顿的刘易斯·西格勒整合基因组学研究所和 马萨诸塞州综合医院，我们的目标是创造变革性的能力并获得最先进的- 艺术研究设施以及培训、教育和推广资源，将吸引不同的人才到 基因组学研究领域。

CENTER FOR GENOME EDITING AND RECORDING: PROJECT SUMMARY Recent advances in DNA sequencing and bioinformatics have generated vast numbers of sequence variants associated with disease that, in principle, hold the keys to breakthroughs in preventive medicine and therapeutic intervention. However, realizing the promise of personalized medicine will require accurate manipulation of DNA sequences and gene expression as well as interrogation of the functional consequences of sequence variants at a scale and level of accuracy not currently possible. The Center for Genome Editing and Recording (CGER) will address these challenges by creating technologies to detect, alter and record the sequence and output of the genome in individual cells and tissues. The CGER will exploit the programmable DNA binding and nickase activity of CRISPR-Cas proteins as well as engineered zinc finger and TALE proteins to create a new generation of tools to precisely engineer the genome and epigenome. These platforms will enable high-precision engineering of both the nuclear and mitochondrial genomes as well as heritable silencing or activation of messenger RNAs, long noncoding RNA and a host of other regulatory elements such as enhancers and insulator regions. Critically, these alterations can be made without introducing double stranded breaks to DNA, thereby avoiding DNA toxicity and minimizing reliance on complex and difficult-to-control endogenous DNA repair pathways. Collectively, these technologies will usher in a new era of safer, high precision and multiplexed genome and epigenome editing. In addition, we will exploit these platforms to develop higher-level multichannel molecular recorders that will allow us to track and reconstruct the life history of cells in an in vivo setting. We will add the ability to follow cells in space and time as well as record the history of their past cellular states to the existing phylogenetic lineage tracing systems pioneered in the previous embodiment of this Center. The center will be led by a team that collectively has a remarkable track record of developing bold, impactful new tools to expand their precision, efficacy, safety and scope, and finally exploiting these new capabilities to develop novel strategies to explore fundamental biological and biomedical problems. Our multidisciplinary team has a rich history of working together, which has been greatly accelerated by the CEGS structure in a manner that would simply not be possible if each co-PI had been working on similar problems in isolation. Leveraging the capabilities of the Whitehead Institute, MIT, The Broad Institute, Harvard University, Harvard Medical School, The Lewis Sigler Institute for Integrative Genomics at Princeton and the Massachusetts General Hospital, we aim to create transformative capabilities and have access to state-of-the- art research facilities as well as resources for training, education and outreach that will attract diverse talent to the field of genomics research.