Polymer models of mitotic and interphase chromosomes

有丝分裂和间期染色体的聚合物模型

基本信息

批准号：
10251068
负责人：
Leonid A Mirny
金额：
$ 34.29万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251068
关键词：
3-Dimensional Affect Affinity Biological Biological Process Cell Nucleus Cells Chromatin Chromosome Structures Chromosome Transfer Chromosomes Chromosomes, Human, 4-5 Collaborations Complex Computer Simulation DNA Data Defect Elements Enhancers Eukaryotic Cell Funding Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Genome Stability Genomic Segment Genomics Goals Hi-C Human Human Genome In Vitro Interphase Chromosome Label Learning Maintenance Malignant Neoplasms Mediating Methods Microscopy Mitosis Mitotic Chromosome Modality Modeling Molecular Nature Nucleosomes Polymerase Polymers Process Resolution Role Side Structural Models Structure Techniques Testing Time Transcript Transcription Process Variant arm chromosome conformation capture cohesin condensin experimental study genetic information genome-wide genomic data human disease in vivo live cell imaging live cell microscopy mutant novel segregation simulation single molecule theories

项目摘要

PROJECT SUMMARY The spatial organization of chromosomes has long been connected to their polymeric nature and is believed to be important for their biological functions, including the control of interactions between genomic elements, the maintenance of genetic information, and the compaction and safe transfer of chromosomes to cellular progeny. Chromosome conformation capture techniques, particularly Hi-C, and microscopy have provided a comprehensive picture of spatial chromosome organization and revealed new features and elements of chromosome folding. Polymer models and new perturbation data generated in the last two years have led to the identification of novel molecular mechanisms behind large-scale genome organization. Two major mechanisms discovered in the course of this project have moved the field forward. First, is the active (ATP-dependent) process of loop extrusion by Structural Maintenance of Chromosomes (SMC) complexes. This universal mechanism underlies formation of domains in the interphase, and chromosome compaction and segregation in mitosis. Second, is the affinity-mediated interactions between heterochromatic regions that drive spatial compartmentalization of the genome at the scale of the whole nucleus. Proposed project aimed at examining mechanisms of loop extrusion, understanding how gene expression and affect extrusion and hence refold chromosomes, and, finally, developing methods to detect loop extrusion in vivo by combination of polymer simulations and live cell imaging. Together, these aims could show whether and how loop extrusion operates in vivo, opening avenues to understand it functional roles and molecular mechanisms.

项目概要染色体的空间组织长期以来一直与其聚合体有关性质，并被认为对其生物功能很重要，包括控制基因组元素之间的相互作用，遗传信息的维护，以及染色体的压缩和安全转移到细胞后代。染色体构象捕获技术，特别是 Hi-C 和显微镜技术提供了空间染色体组织的全面图景并揭示新特征和染色体折叠的元素。聚合物模型和新的扰动数据过去两年产生的新分子已被鉴定出来大规模基因组组织背后的机制。两大机制该项目过程中的发现推动了该领域的发展。首先，是主动的通过染色体结构维护进行环挤出的（ATP 依赖性）过程（SMC）复合物。这种通用机制是域形成的基础间期，以及有丝分裂中的染色体压缩和分离。其次，是驱动空间的异色区域之间亲和力介导的相互作用在整个细胞核尺度上对基因组进行划分。建议的项目旨在研究环挤出机制，了解基因如何表达并影响挤出，从而重新折叠染色体，最后发育结合聚合物模拟和活体检测体内环挤出的方法细胞成像。总之，这些目标可以表明环挤出是否以及如何进行在体内运作，为了解其功能作用和分子机制开辟了途径机制。