Three-Dimensional Structure of Eukaryote Chromosomes

染色体的三维结构是细胞科学中最丰富的未探索领域。 染色体是所有细胞中最大、最有活力和最复杂的 细胞器它们是最基本的，潜在的细胞分化，细胞生理学， 和疾病它们也是最神秘的，同时表现出结构上的 异质性和秩序，身体的灵活性和刚性，以及功能活动， 沉默我们将通过确定染色体结构来解开这些谜团。 目前对染色体结构几乎一无所知。然而 染色体结构是染色体功能的关键;它与所有 DNA处理，表观遗传学，以及疾病中的畸变。 我们提出了一个全面的解决方案的染色体结构问题。我们将 追踪染色质纤维的路径，从核小体到核小体，通过TADs 和中间区域。我们将在单个核小体分辨率下“行走”3D基因组。 我们将采用超分辨率光学显微镜与DNA序列特异性染料 分子（荧光发射器）的目的。分辨率为10-20 nm， 与核小体的大小（10 nm）相当的核小体通常用电流实现。 显微镜.发射体到单个核小体的定位可以是 通过使用专门设计的吡咯-咪唑聚酰胺和锌 指状蛋白这些分子一旦被设计出来， 在所有类型的细胞中，在细胞周期的所有阶段，在正常的 和疾病状态。他们将通过提供结构化范例来改变这个领域， 通过使其他人能够解决遗传化学和生物学中的无数问题， 一种轻松、敏锐的方式。 !

The 3-D structure of chromosomes is the richest unexplored territory in cell science. Chromosomes are the largest, most dynamic, and most complex of all cellular organelles. They are most fundamental, underlying cell differentiation, cell physiology, and disease. They are also most enigmatic, exhibiting at the same time structural heterogeneity and order, physical flexibility and rigidity, and functional activity and silencing. We will dispel the mysteries by the determination of chromosome structure. Virtually nothing is known about chromosome structure at the present time. And yet chromosome structure is the key to chromosome function; it is inextricably linked to all DNA transactions, to epigenetics, and to aberrations in disease. We propose a comprehensive solution of the chromosome structure problem. We will trace the path of the chromatin fiber, from nucleosome to nucleosome, through TADs and intervening regions. We will "walk" the 3-D genome at single nucleosome resolution. We will employ super resolution light microscopy with DNA sequence-specific dye molecules (fluorescence emitters) for the purpose. A resolution of 10-20 nm, comparable to the size of a nucleosome (10 nm) is routinely achieved with current microscopes. The localization of an emitter to an individual nucleosome can be accomplished with the use of specially designed pyrrole-imidazole polyamides and zinc finger proteins. These molecules, once designed, will be applicable to chromosome structure determination in all types of cell, at all stages of the cell cycle, in both normal and disease states. They will transform the field, by providing structural paradigms, and by enabling others to address innumerable problems in genetic chemistry and biology in a facile, penetrating manner. !