Multiplexed imaging of chromatin folding and RNA profiles in cancer

项目总结/摘要 在细胞核中，基因组的三维（3D）折叠调节许多基因组功能， 从基因表达调控到DNA复制、重组和修复。3D基因组结构 存在于各种长度尺度上，并且已知基因组结构的变化与癌症相关， 而是在异质性肿瘤中癌细胞基因组折叠的真实物理图像 微环境仍然难以捉摸。也不知道3D基因组组织的变化如何影响 肿瘤中的单细胞基因表达。现有的基于测序的组学方法无法解决这些问题。 由于技术上的限制。在这里，我们提出了一个新的先进的开发和验证， 成像方法，可以直接追踪跨多个长度尺度的基因组的空间折叠， 在同一个单细胞中以单分子分辨率成像许多RNA种类， 肿瘤的我们将用小鼠肿瘤模型来测试这种方法，这些模型能够在移植过程中追踪癌症克隆的谱系。 进展和来自人类患者的临床样品。我们希望这种技术进步能够改变 癌症生物学中的3D基因组研究，并为癌症诊断，预后和治疗提供新的生物标志物。 治疗

Project Summary/Abstract In the cell nucleus, the three-dimensional (3D) folding of the genome regulates many genomic functions, ranging from gene expression regulation to DNA replication, recombination, and repair. 3D genomic structures exist at a variety of length scales, and changes in genome structures are known to be associated with cancer, but a true physical picture of genome folding in cancer cells within their heterogeneous tumor microenvironment is still elusive. It is also unknown how variations of the 3D genome organization may affect single-cell gene expression in tumors. Existing sequencing-based omics approaches cannot address these questions due to technical limitations. Here we propose the advanced development and validation of a new imaging method that can directly trace the spatial folding of the genome across multiple length scales and image numerous RNA species with single-molecule resolution in the same single cells in heterogeneous tumors. We will test this method with mouse tumor models that enable lineage tracing of cancer clones during progression and with clinical samples from human patients. We expect this technologic advance to transform 3D genome investigation in cancer biology and lead to new biomarkers for cancer diagnosis, prognosis, and treatment.