Center for Genome Imaging

项目概要/摘要 基因组成像中心（CGI） 目的：三维（3D）基因组组织是基因组功能的主要贡献者， 然而，我们只是在发现其背后的结构特征的黎明， organization.因此，拟议研究的目标是开发和应用工具，使自我- 人类基因组的序列特异性成像，在其整体上，具有高基因组分辨率。尤其是- 最后，拟议的工作将创新的方法，固定和活细胞成像使用衍射限制光 显微镜和超分辨率显微镜，以及开发新的工具，图像分析和ge- nome建模。为此，它将涉及四个实验室的持续合作，其共同点是： 专业知识的选择范围涵盖经典和分子遗传学，染色体动力学， 集成电路、成像、Hi-C分析、卷积神经网络和基于聚合物物理的约束- 基于建模。拟议研究的另一个同样重要的目标是确保产生再生能源， 他们的个人专业知识广度将与整个当前团队相匹配。 健康相关性：对3D基因组组织的坚实把握是否会对 人的发展？是否有助于保护人类健康？它会有助于 早期诊断的策略，甚至是新疗法的开发？一切的答案 这些问题几乎肯定是一个响亮的是，作为3D基因组组织的知识将en- 增强我们应对基本生物过程和疾病的能力。 创新：大量的研究认为，基因组作为一个完整的单位发挥作用，然而， 现有技术能够以高基因组分辨率对整个基因组进行序列特异性成像。 因此，研究人员的能力，以了解三维基因组组织和基因组之间的相互作用， nome的功能已被限制为局部事件的不连贯的快照。因此，前三个目标 将开发下一层工具，将整个基因组放在触手可及的范围内。他们将提出一种新方法， OligoFISSEQ，然后将其与OligoSTORM和OligoDNA-PAINT整合，以最终实现高- 常规和超分辨率的吞吐量成像。他们还将解决两个基因组fea- 已经非常难以捕获的结构-二倍体细胞中存在同源物， 重复序列-以及用于大容量数据存储、图像处理的创新策略 and analysis分析，and modeling建模.最后，第四个目标是实施传播我们工具的方法。 1.面向全基因组成像的扩展技术 2.填补空白以可视化染色体端到端-处理同源物和重复序列 3.探针设计、图像分析、建模和表观遗传数据的整合 4.全基因组成像领域的培训、资源和机会

Project Summary/Abstract Center for genome imaging (CGI) Objectives: Three-dimensional (3D) genome organization is a major contributor to genome func- tion, and yet, we are only at the very dawn of discovering the structural signatures that underlie that organization. Thus, the goal of the proposed studies is to develop and apply tools that will enable se- quence-specific imaging of human genomes, in their entirety, with high genomic resolution. In particu- lar, the proposed work will innovate methods for fixed and live cell imaging using diffraction-limited light microscopy and super-resolution microscopy as well as develop new tools for image analysis and ge- nome modeling. To this end, it will involve the continued collaboration of four laboratories, whose col- lective breadth of expertise covers the fields of classical and molecular genetics, chromosome dynam- ics, imaging, Hi-C analysis, convolutional neural networks, and polymer physics-based and restraint- based modeling. An equally important objective of the proposed studies is to ensure a generation of re- searchers whose personal breadth of expertise will come to match that of the entire current team. Health relatedness: Will a solid grasp of 3D genome organization have implications for under- standing human development? Will it contribute to the protection of human health? Will it contribute to strategies for early diagnostics and perhaps even the development of new therapies? The answer to all these questions is almost certainly a resounding Yes, as knowledge of 3D genome organization will en- hance our capacity to address both fundamental biological processes as well as disease. Innovation: An abundance of studies argue that genomes function as integrated units and, yet, no extant technologies enable sequence-specific imaging of entire genomes at high genomic resolution. Thus, the capacity of researchers to fathom the interplay between 3D genome organization and ge- nome function has been limited to disjointed snapshots of localized events. Accordingly, first three aims will develop the next tier of tools to put entire genomes within reach. They will advance a new method, OligoFISSEQ, and then integrate it with OligoSTORM and OligoDNA-PAINT to finally achieve high- throughput imaging at both conventional and super-resolution. They will also tackle two genomic fea- tures that have been prohibitively difficult to capture – presence of homologs in diploid cells and highly repeated sequences – as well as innovate strategies for high volume data storage, image processing and analysis, and modeling. Finally, a fourth aim will implement methods for disseminating our tools. 1. Scaling technologies toward whole genome imaging 2. Filling in gaps to visualize chromosomes end-to-end – tackling homologs and repeats 3. Probe design, image analysis, modeling, and integration of epigenetic data 4. Training, resources, and opportunities for engaging colleagues in whole genome imaging