Assembly and epigenetic inheritance of the human centromere

人类着丝粒的组装和表观遗传

基本信息

批准号：
9119625
负责人：
Daniel Richard Foltz
金额：
$ 29万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2015-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119625
关键词：
Acetylation Aneuploidy Area Biological Assay Biotin Cell Survival Cell division Cells Centromere Chromatin Chromatin Modeling Chromosomal Instability Chromosome Segregation Chromosomes Complex Coupled DNA Sequence DNA biosynthesis DNA replication fork Data Deposition Development Elements Ensure Epigenetic Process Eukaryota Event Genomic Instability Goals Health Histone H3 Histones Human In Vitro Kinetochores Lead Ligase Ligation Location Malignant Neoplasms Mass Spectrum Analysis Mediating Methylation Mitosis Mitotic Modification N-terminal Nucleosomes Pathway interactions Phosphorylation Phosphotransferases Positioning Attribute Post-Translational Protein Processing Process Proteins Recruitment Activity Regulation Research Role S Phase Serine Structure Tail Techniques Testing Time Variant Work centromere protein A combinatorial insight interest novel reconstitution research study tumor progression

项目摘要

DESCRIPTION (provided by applicant): The centromere is a unique chromatin domain defined by the incorporation of a centromere specific nucleosome containing centromere protein-A (CENP-A). The centromere recruits the mitotic kinetochore to ensure the equal segregation of chromosomes during mitosis. The location of the centromere along the chromosome is determined by an epigenetic mechanism that relies on the CENP-A nucleosome. New CENP-A nucleosomes are assembled into the centromeres of dividing cells during a discreet time in early G1. Propagation of the centromere requires assembly of new CENP-A nucleosomes prior to DNA replication to avoid the loss of CENP-A nucleosomes through their successive dilution. Previously we determined Mis18 complex recruitment is the defining step in epigenetic inheritance. This proposal will explore the mechanism by which new CENP-A is recruited to centromeres through the recruitment of the Mis18 complex. Canonical histones are subject to multiple posttranslational modifications (PTMs) that drive the recruitment of chromatin associated factors and modify the function of the underlying chromatin. We will explore the function of two newly identified PTMs of the CENP-A tail, amino-terminal trimethylation and dual phosphorylation of serine 16 and 18. The experiments proposed here will significantly advance our understanding of the epigenetic mechanism of centromere inheritance. Furthermore, the impact of this work will extend beyond the centromere to provide significant insight into the propagation of epigenetic information encoded by acetylation and methylation or other histone variants.

描述（由申请人提供）：着丝粒是一个独特的染色质结构域，通过掺入含有着丝粒蛋白-A (CENP-A) 的着丝粒特异性核小体来定义。着丝粒募集有丝分裂着丝粒以确保有丝分裂期间染色体的平等分离。着丝粒沿染色体的位置由依赖于 CENP-A 核小体的表观遗传机制决定。新的 CENP-A 核小体在 G1 早期的一段谨慎时间内组装到分裂细胞的着丝粒中。着丝粒的增殖需要在 DNA 复制之前组装新的 CENP-A 核小体，以避免 CENP-A 核小体因连续稀释而丢失。之前我们确定 Mis18 复合体招募是表观遗传的决定性步骤。该提案将探讨通过招募 Mis18 复合体将新 CENP-A 招募到着丝粒的机制。典型组蛋白会受到多种翻译后修饰 (PTM) 的影响，这些修饰会促进染色质相关因子的募集并改变底层染色质的功能。我们将探索CENP-A尾部两个新发现的PTM的功能，即氨基末端三甲基化以及丝氨酸16和18的双重磷酸化。这里提出的实验将显着推进我们对着丝粒遗传的表观遗传机制的理解。此外，这项工作的影响将扩展到着丝粒之外，为乙酰化和甲基化或其他组蛋白变体编码的表观遗传信息的传播提供重要的见解。