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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：
10018877
负责人：
MICHAEL LEVITT
金额：
$ 144.01万
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/10018877
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. !

染色体的三维结构是细胞科学中最丰富的未知领域。染色体是所有细胞中最大、最有活力、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，同时表现出结构性的异质性和有序性，身体的柔韧性和刚性，以及功能活动和沉默。我们将通过染色体结构的测定来解开谜团。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交易、表观遗传学和疾病中的异常。我们提出了染色体结构问题的一个综合解决方案。我们会通过TADS追踪染色质纤维从核小体到核小体的路径以及相互影响的区域。我们将以单核小体分辨率“行走”3-D基因组。我们将使用超分辨率光学显微镜和dna序列特异性染料。分子(荧光发射体)用于此目的。10-20纳米的分辨率，与核小体的大小(10 Nm)相当，通常是通过电流实现的显微镜。发射体对单个核小体的定位可以是使用特别设计的吡咯咪唑聚酰胺和锌手指蛋白。这些分子一旦被设计出来，就会应用到染色体上。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。它们将通过提供结构范例来改变这一领域，并通过使其他人能够解决遗传化学和生物学中的无数问题轻快、敏锐的态度。好了！