Three-Dimensional Structure of Eukaryote Chromosomes

真核生物染色体的三维结构

基本信息

批准号：
9789272
负责人：
ROGER D KORNBERG
金额：
$ 162.64万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789272
关键词：
3-Dimensional Address Adopted Amphibia Base Sequence Biological Biology Caliber Cell Cycle Stage Cell Differentiation process Cell physiology Cells Chemicals Chemistry Chromatin Chromatin Fiber Chromatin Loop Chromosome Condensation Chromosome Structures Chromosomes Complex Cytology DNA DNA Sequence DNA Structure Dimensions Disease Drosophila genus Dyes Epigenetic Process Eukaryota Exhibits Fluorescence Frequencies Gene Expression Gene Expression Regulation Genetic Genome Health Heterogeneity Histones Human Human Genome Imidazole Individual Interphase Knowledge Larva Length Light Link Malignant Neoplasms Maps Measures Meiosis Methods Microscope Mitosis Mitotic Chromosome Molecular Nucleosomes Nylons Organelles Pattern Proteins Pyrroles Reporting Research Resolution Science Site Structure Time Transact Walking Zinc Fingers alpha helix base cell type crosslink design flexibility gene induction gene repression innovation insight light microscopy novel therapeutics protein distribution repaired structural biology three dimensional structure virtual

项目摘要

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. !

染色体的3-D结构是细胞科学中最丰富的未开发领域。染色体是所有细胞中最大，最动态和最复杂的染色体细胞器。它们是最基本的，潜在的细胞分化，细胞生理，和疾病。它们也是最神秘的，同时展示了结构异质性和秩序，身体灵活性和刚性以及功能活动以及沉默。我们将通过确定染色体结构来消除奥秘。实际上，目前对染色体结构一无所知。但是染色体结构是染色体功能的关键。它与所有人无关 DNA交易，表观遗传学和疾病的畸变。我们提出了染色体结构问题的全面解决方案。我们将通过TADS追踪从核小体到核小体的染色质纤维的路径和干预区域。我们将以单核小体分辨率“行走” 3-D基因组。我们将使用DNA序列特异性染料采用超级分辨率显微镜为此目的，分子（荧光发射器）。 10-20 nm的分辨率，与核小体（10 nm）的大小相当显微镜。发射极在单个核小体中的定位可以是通过使用特殊设计的吡咯 - 咪唑聚酰胺和锌来完成手指蛋白。这些分子曾经设计，将适用于染色体在两个正常情况下，在细胞周期的所有阶段，所有类型的细胞的结构测定和疾病状态。他们将通过提供结构范例来改变领域，并通过使他人能够解决遗传化学和生物学中无数的问题一种便捷的穿透方式。呢