Dicentric chromosome formation and stability in humans

人类双着丝粒染色体的形成和稳定性

基本信息

批准号：
8616075
负责人：
BETH A SULLIVAN
金额：
$ 30.59万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616075
关键词：
Address Affect Aging Agriculture Aneuploidy Animal Model Behavior Biological Assay Biological Models Cell division Cells Centromere Chromatids Chromatin Chromosomal Stability Chromosome Segregation Chromosome Structures Chromosomes Chromosomes, Human, 4-5 Complex Congenital Abnormality DNA DNA Sequence DNA Sequence Rearrangement Data Dicentric chromosome Disease Down Syndrome Engineering Ensure Epigenetic Process Experimental Models Frequencies Functional disorder Gene Cluster General Population Genetic Genome Genome Stability Genomic Instability Genomics Goals Human Human Chromosomes Incidence Infertility Knowledge Laboratory Study Link Maize Malignant Neoplasms Meiosis Mitosis Mitotic Modeling Molecular Organism Outcome Pathway interactions Patients Population Process Proteins Recurrence Regulation Repression Research Role Specific qualifier value Spontaneous abortion System Testing Therapeutic Time Work arm base cancer therapy chromosome movement insight novel rRNA Genes reproductive segregation transmission process vector

项目摘要

DESCRIPTION (provided by applicant): Chromosome inheritance ensures transmission of genetic and genomic information. Abnormal chromosome number (aneuploidy) and altered chromosome structure cause birth defects, reproductive abnormalities, and cancer. The centromere is the locus required for chromosome segregation and genome stability. Normal chromosomes typically have one centromere, but genome rearrangements associated with birth defects and cancer produce chromosomes in which two centromeres are physically linked. These dicentrics are not naturally tolerated in most model organisms, as originally illustrated in maize by Barbara McClintock nearly 75 years ago. In humans, dicentric chromosomes occur non-randomly and can be extremely stable during cell division. Such stability has been attributed to centromere inactivation, the poorly understood process by which one centromere is functionally suppressed. Our goal is to define molecular pathways responsible for dicentric formation and long-term stability. We hypothesize that (A) formation of common dicentrics is linked to genomic features of acrocentric chromosomes, and (B) centromere inactivation routinely occurs by either genomic or epigenetic mechanisms. A major impediment in studying centromere inactivation in humans has been the absence of experimental systems. To circumvent this long-standing problem, we have developed assays to engineer dicentric human chromosomes that molecularly mirror those that occur naturally. Engineered dicentrics represented a model system to study normal centromere function, centromere repression and genome stability. Using these experimental models, we propose three specific aims: 1) To identify sequence-dependent mechanisms of dicentric formation, 2) To define the molecular pathways by which dicentric chromosomes are stabilized, including genomic, epigenetic and temporal changes associated with centromere inactivation, and 3) To experimentally test models of centromere inactivation using protein tethering and engineered genomic deletions. Collectively, these studies will define the mechanistic basis for non-random participation of acrocentric chromosomes in naturally occurring and experimentally produced chromosome fusions. Our studies will also be critical for evaluating current models of centromere function, and provide new insights into mechanisms that specify and maintain centromeres on human chromosomes.

描述（由申请人提供）：染色体遗传确保遗传和基因组信息的传播。异常的染色体数（非整倍）和染色体结构改变会导致先天缺陷，生殖异常和癌症。丝粒是染色体分离和基因组稳定性所需的基因座。正常染色体通常具有一个丝粒，但是与先天缺陷和癌症相关的基因组重排会产生染色体，其中有两个centromeres在物理上与之相连。在大多数模型生物体中，这些dicentrics在大多数模型生物中都不容忍，正如芭芭拉·麦克林托克（Barbara McClintock）最初在近75年前所说的那样。在人类中，二含染色体出现非随机性，在细胞分裂过程中可能非常稳定。这种稳定性已归因于中心灭活，这是一个在功能上被抑制的一个丝粒的知识较低的过程。我们的目标是定义负责二分位数形成和长期稳定性的分子途径。我们假设（a）共同双齿的形成与基因组染色体的基因组特征有关，并且（b）丝粒灭活通常是通过基因组或表观遗传机制发生的。研究人类中的丝粒失活的主要障碍是没有实验系统。为了避免这个长期存在的问题，我们开发了测定方法，以设计分子染色体，这些染色体可以反映出天然发生的染色体。工程化的双齿代表了一个模型系统，用于研究正常的丝粒功能，丝粒抑制和基因组稳定性。使用这些实验模型，我们提出了三个具体目的：1）确定二齿形成的序列依赖性机制，2）定义稳定二口染色体的分子途径，包括稳定的牙齿染色体，包括与centromere灭绝的基因构成模型相关的基因，表观遗传学和时间变化，以及3）的基于型号的模型，以及3）删除。总的来说，这些研究将定义非随机参与自然发生和实验产生的染色体融合的机理基础。我们的研究对于评估当前的丝粒功能模型以及对指定和维持人类染色体的centromeres的机制提供新的见解也将是至关重要的。