Centromere identity, strength, and regulation

着丝粒的身份、强度和调节

• 批准号: 9896871
• 负责人: Ben E. Black
• 金额: $ 56.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896871
• 关键词: Adult; Aneuploidy; Area; Automobile Driving; Biochemical; Biological; Biophysics; Cell division; Cells; Centromere; Chromatin; Chromosome Segregation; Chromosomes; Chromosomes, Artificial, Human; Congenital Abnormality; DNA; DNA Sequence; Defect; Disease; Ensure; Epigenetic Process; Equilibrium; Eukaryota; Evolution; Gene Dosage; Genetic; Genome; Germ Cells; Human; Knowledge; Malignant Neoplasms; Mammals; Medical; Mitosis; Mitotic; Mitotic Chromosome; Molecular; Newborn Infant; Pathway interactions; Play; Process; Proteins; Quality Control; Regulation; Role; Satellite DNA; Science; Sister; Spontaneous abortion; Time; Work; daughter cell; embryo/fetus; epigenomics; genetic information; insight; mouse model; physical property; quantum; reconstitution; success; tumor

Project Summary/Abstract Defects in the equal partitioning of chromosomes at cell division causes aneuploidy, a genetic catastrophe that results in spontaneous abortion or birth defects if it arises in the gametes and that is a major contributor to gene dosage imbalances in almost all human cancers. The centromere is the locus on each chromosome that directs accurate chromosome segregation at cell division in healthy cells, but a paradox exists in the field because the DNA sequences typically found at the loci are neither necessary nor sufficient for centromere function. As our major area of contribution to science, thus far, we have made major headway during the past decade in elucidating the molecular basis for centromere identity, the epigenetic pathway that propagates centromeric chromatin in perpetuity, the relationship between epigenetic and genetic information in driving centromere evolution in eukaryotes, and key steps in the quality control pathway that ensures proper chromosome segregation at cell division. In the next five years, we are poised to make quantum leaps in our molecular understanding of centromeres in three areas. The first area is with a new type of human artificial chromosome (HAC) that we have recently developed. We will gain new insight regarding the relationship between DNA sequence and centromere formation and expand the utility of HACs in experimental and applied settings. The second area is with mouse models and biochemical reconstitution to expand our understanding of the balance of epigenetics and genetics at the centromere. We will build on our success with gaining the first molecular evidence in mammals of an evolutionary process known as “centromere drive” to now define the relationship of this process to the expansion of centromeric satellite DNA sequences. In addition, we will investigate the role of the centromere repeats typically found at human centromeres on the physical properties of centromeric chromatin using purified components. The third area is with a combination of biophysical, cell biological, and epigenomic approaches to extend our understanding of centromere regulation at mitosis. We will focus on the chromatin at the “inner centromere” (i.e. between the pair of sister centromeres on a mitotic chromosome) that plays a key role in the quality control step known as mitotic error correction. Altogether, our progress in these three areas will constitute a major advance in our understanding of the molecular mechanisms underlying the specification and regulation of centromeres.

项目摘要/摘要 细胞分裂染色体平等分配的缺陷会导致非整倍性，这是一种遗传灾难，是一种遗传灾难 如果游戏中出现赞助堕胎或出生缺陷，则会导致游戏中的主要因素 几乎所有人类癌症的基因剂量失衡。中心仪是每个染色体上的基因座 指导健康细胞中细胞分裂的准确染色体分离，但在现场存在悖论 因为通常在局部发现的DNA序列既不需要，也不足够 功能。作为我们对科学的主要贡献，到目前为止，我们过去取得了重大进展 十年阐明了丝粒身份的分子基础，这是传播的表观遗传途径 centromeric染色质永久性，表观遗传和遗传信息之间的关系 真核生物中的Centromere进化，以及质量控制途径的关键步骤，以确保正确 细胞分裂的染色体分离。在接下来的五年中，我们被中毒以在我们的 分子对三个区域中的丝粒的理解。第一个区域是一种新型的人造类型 我们最近开发的染色体（HAC）。我们将获得有关关系的新见解 在DNA序列和丝粒形成之间，并扩展了HAC在实验中的实用性和应用 设置。第二个领域是鼠标模型和生化重构，以扩大我们的理解 丝粒表观遗传学和遗传学的平衡。我们将在获得第一个的基础上取得成功 哺乳动物中的分子证据被称为“ Centromere Drive”，以定义 该过程与中心卫星DNA序列的扩展。此外，我们将 研究通常在人体丝粒物理特性上的中心粒重复序列的作用 使用纯化的成分的丝粒染色质。第三个区域是生物物理，细胞的组合 生物学和表观基因组学方法，以扩展我们对有丝分裂时丝粒调节的理解。我们 将重点放在“内侧丝粒”的染色质上（即有丝分裂的姐妹centromeres之间 染色体）在称为有丝分裂误差校正的质量控制步骤中起关键作用。总共，我们的 这三个领域的进展将构成我们对分子的理解的重大进步 丝粒规范和调节的基础机制。