Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease

项目概要/摘要： 人类染色体在细胞核内的3D折叠影响了许多基本的生物学过程， 包括基因调控、DNA修复和复制，甚至细胞核的物理性质。最近 研究开始确定构建基因组结构的关键分子因子，但所知甚少 关于这个结构如何对细胞和细胞核所经历的物理压力做出反应。3D基因组 健康细胞中的结构必须承受或响应于诸如物理力、核形状 变化和DNA损伤的侮辱，如辐射。基因组结构和核结构的破坏 可能导致癌症或过早衰老等疾病，因此我们确定其特征非常重要， 3D基因组变化的原因和影响。通常，3D基因组组织中与疾病相关的变化是 孤立地考虑，即“这种变化发生在癌症中”，但这种观点可能会错过共同的基础， 在许多生物情况下控制3D基因组的机制。我的研究计划旨在 发展一个综合的观点，染色体的变化经验，以响应物理破坏 通过一系列互补的项目。我们的首要目标是了解不同层次的3D 基因组结构的变化，以响应核形状的变化和DNA损伤辐射，以及如何 基因组中的3D接触网络可以实现基因调控功能，并有助于 原子核的必要物理性质。为此，我们将整合显微镜，尖端 基于测序的技术，如染色体构象捕获（Hi-C），和计算 研究几种系统中3D基因组破坏的方法，包括：1）暴露于DNA的细胞 破坏性的X射线照射，2）细胞核所必需的3D基因组的初始状态和适应， 在有限的迁移过程中挤压通过紧密的空间，和3）基因组结构的方面， 在核纤层蛋白突变的早衰细胞中细胞老化期间被破坏和维持。我们的研究计划 初步的证据激发了对这些系统的进一步研究：我们已经确定， 在X射线损伤后积极保护其3D基因组结构，并且3D基因组折叠状态影响 癌细胞核是否能在转移迁移过程中挤压通过狭窄的空间。这些结果表明 对基因组结构变化的全面了解对于更好地了解疾病是必要的， 启动和进展。跨系统分析基因组结构变化将提供一个独特的， 什么类型的基因组区域或结构是最强大或最脆弱的， 在不同长度尺度上的基因组结构之间的依赖性。所有这些结果将帮助我们建立一个 我们可以理解并最终预测某些治疗或条件的影响的框架 对人类细胞类型的影响，取决于它们最初的基因组折叠状态。这一框架将为以下方面开辟道路： 未来基于染色体结构的疾病诊断和治疗。

Project Summary/Abstract: The 3D folding of human chromosomes inside the nucleus affects numerous fundamental biological processes, including gene regulation, DNA repair and replication, and even the physical properties of the nucleus. Recent research is beginning to define the key molecular factors that build the genome structure, but little is known about how this structure responds to physical stresses experienced by cells and nuclei. The 3D genome structure in healthy cells must withstand or respond to perturbations such as physical forces, nuclear shape changes, and DNA damaging insults, like radiation. Disruptions in genome structure and nuclear architecture can lead to diseases such as cancer or premature aging, so it is important that we determine the characteristics, causes, and effects of 3D genome changes. Often, disease-related changes in 3D genome organization are considered in isolation, i.e. “this change occurs in cancer,” but this perspective may miss common underlying mechanisms that govern the 3D genome across many biological situations. My research program seeks to develop an integrative view of the changes that chromosomes experience in response to physical disruptions through a complementary set of projects. Our overarching goals are to understand how different levels of 3D genome structure change in response to nuclear shape changes and DNA damaging radiation and how the network of 3D contacts in the genome can accomplish both gene regulatory functions and contribute to necessary physical properties of the nucleus. To this end, we will integrate microscopy, cutting edge sequencing-based techniques such as chromosome conformation capture (Hi-C), and computational approaches to investigate 3D genome disruptions in several systems, including: 1) cells exposed to DNA damaging X-ray irradiation, 2) the initial states and adaptations of the 3D genome necessary for cell nuclei to squeeze through tight spaces during confined migration, and 3) the aspects of genome structure that are disrupted and maintained during cellular aging in a lamin-mutant progeria cell. Our research program has yielded preliminary evidence that motivates further study of these systems: we have determined that the cell actively protects its 3D genome structure after X-ray damage and that the 3D genome folding state influences whether cancer cell nuclei can squeeze through tight spaces during metastatic migration. These results show that a comprehensive understanding of genome structure changes is necessary to better understand disease initiation and progression. Analyzing genome structure changes across systems will provide a unique, integrated view of what types of genomic regions or structures are the most robust or fragile and the degree of dependence between genome structures at different length scales. All these results will help us build a framework in which we can understand, and eventually predict, the impact of certain treatments or conditions on human cell types, depending on their initial genome folding state. This framework will open avenues for future chromosome structure-based disease diagnosis and treatment.