Polymer models of mitotic and interphase chromosomes

 描述(申请人提供)：染色体的三维(3D)组织越来越被认为是基因调控和基因组稳定性的关键决定因素，而染色体组织失调是许多疾病的标志，最突出的是癌症。健康细胞的空间基因组结构及其在细胞周期、发育和分化过程中的变化仍然是个谜。基因组技术的最新进展，特别是5C和Hi-C等染色体构象捕获方法的发展，使得通过全面绘制染色质远程相互作用图来探测染色体的空间组织成为可能。然而，进一步的进展仍然缓慢，部分原因是Hi-C数据和可以揭示基因组折叠原理的染色体组织3D模型之间的差距。Hi-C数据和染色体聚合物模型之间的桥梁是一个重大挑战，也是我们研究计划的一个目标。最近，我们开发了分析Hi-C数据的方法，并成功地建立了人类有丝分裂染色体和细菌间期染色体的动态聚合物模型，揭示了数据中无法直接看到的多层次组织和结构元素。在这里，我们建议通过开发不同细胞类型中的人类间期染色体的多尺度模型，以及基于现有的和新兴的全基因组相互作用Hi-C图的有丝分裂凝聚的机制模型，来自然地进行下一步。结合这项工作，有可能极大地加深我们对3D基因组在不同细胞类型和细胞周期中的组织和重组的理解。

 DESCRIPTION (provided by applicant): The three-dimensional (3D) organization of chromosomes is being increasingly appreciated as a critical determinant of gene regulation and genome stability, and dysregulation of chromosome organization is a hallmark of many diseases, most prominently of cancer. Spatial genome architecture in healthy cells and its changes through the cell cycle, development and differentiation remain enigmatic. Recent progress if genomic technologies, particularly development of the Chromosome Conformation Capture methods such as 5C and Hi-C, allowed probing the spatial organization of chromosomes by comprehensive mapping of long-range chromatin interactions. Further progress, however, remains slow in part due to a gap between Hi-C data and 3D models of chromosome organization that can reveal principles of genome folding. Bridging between Hi-C data and polymer models of chromosomes is a major challenge and an objective of our research program. Recently we have developed methods for analysis of Hi-C data, and have successfully developed dynamic polymer models of human mitotic chromosomes and bacterial interphase chromosome, which revealed multiple levels of organization and structural elements not directly visible in the data. Here we propose to make natural next steps by developing multi-scale models of human interphase chromosome in different cell types, and mechanistic models of mitotic condensation that are based on available and emerging genome-wide interaction Hi-C maps. Combined this work has the potential to greatly deepen our understanding of 3D genome organization and reorganization in different cell types and during cell cycle.