Center for 3D Structure and Physics of the Genome

 产品说明：基因组的空间组织影响所有的基因组过程，包括基因调控，基因组稳定性的维持和染色体传递到子细胞。详细了解人类基因组的空间排列，称为4D核组，以及驱动染色体折叠的生物学和物理学原理，需要将分子和细胞生物学，成像，遗传学和基因组学领域的方法与物理学，计算生物学和计算机模拟相结合。我们已经组建了一个高度跨学科的中心，目标是生成4D核组的广泛验证的地图，其物理和动态特性及其在调节基因组活动中的作用。 一是中心将进一步优化， 广泛验证了一套全基因组分子方法，基于染色体构象捕获（3C），可以在单个核小体，染色质纤维，染色体和整个细胞核的规模上，跨细胞群和单细胞探测染色体的折叠。鉴于染色体和核组织与细胞的生物学状态密切相关，该中心将绘制细胞周期（间期和有丝分裂）和细胞分化（多能和分化状态）期间代表不同构象的四种关键生物学状态的4D核组。我们将获得有关染色质的结构和动力学的补充数据，在不同的长度尺度和单细胞使用广泛的高通量成像，活细胞成像和超分辨率显微镜。所有方法获得的数据将使用一组方法进行分析，整合和建模，我们将进一步开发，以深入了解不同长度尺度上染色体折叠的结构，物理和动力学。最后，我们的建议的一个关键组成部分是生物学验证和进一步阐述的染色质相互作用的地图，从我们的构象分析。这种验证将通过基因组序列和表观遗传标记的位点特异性编辑、基因组内新接触点的创建以及促进或限制这些相互作用的因子（蛋白质和核酸）的鉴定来实现。染色体构象的这种扰动对转录的影响将揭示特定染色体结构特征与基因表达之间的关系。

 DESCRIPTION: The spatial organization of the genome impinges on all genomic processes, including gene regulation, maintenance of genome stability and chromosome transmission to daughter cells. A detailed understanding of the spatial arrangement of the human genome, referred to as the 4D nucleome, and the biological and physical principles that drive chromosome folding requires combining approaches from the fields of molecular and cell biology, imaging, genetics and genomics with approaches from physics, computational biology, and computer simulation. We have assembled a highly interdisciplinary center with the goal of generating extensively validated maps of the 4D nucleome, its physical and dynamic properties and its role in regulating the activity of the genome. First, the center will further optimize and extensively validate a suite of genome-wide molecular methodologies, based on chromosome conformation capture (3C) that can probe the folding of chromosomes at the scale of single nucleosomes, chromatin fibers, chromosomes and the entire nucleus, across cell populations and in single cells. Given that chromosome and nuclear organization is tightly linked to biological state of the cell, the center will map the 4D nucleome for four key biological states representing different conformations during the cell cycle (interphase and mitosis), and during cell differentiation (pluripotent and differentiated states). We will obtain complementary data regarding the structure and dynamics of chromatin, at different length scales and in single cells using extensive high-throughput imaging, live cell imaging and super resolution microscopy. Data obtained with all approaches will be analyzed, integrated and modeled using a set of methods we will further develop to gain insights into the structure, physics and dynamics of chromosome folding over different length scales. Finally, a critical component of our proposal is the biological validation and further elaboration of the chromatin interaction maps that are generated from our conformational analyses. This validation will be achieved through site-specific editing of genomic sequence and epigenetic marks, the creation of new contact points within the genome, and the identification of factors (both protein and nucleic acid) that facilitat or restrict these interactions. Effects of such perturbations in the chromosome conformation on transcription will reveal relationships between specific chromosome structural features and gene expression.