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Ectopic centromere assembly in humans

人类异位着丝粒组装

基本信息

批准号：
10059192
负责人：
BETH A SULLIVAN
金额：
$ 22.58万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059192
关键词：
Address Animal Model Biological Biological Assay Biological Models Biology Cell division Cells Centromere Chicken Cells Chromatin Chromatin Structure Chromosome Arm Chromosome Breakage Chromosome Markers Chromosome Segregation Chromosome abnormality Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Congenital Abnormality DNA DNA Damage Disease Drosophila genus Engineering Environment Euchromatin Event Excision Gene Expression Genetic Transcription Genome Genome Stability Genome engineering Genomic Instability Genomic Segment Genomics Heterochromatin Histones Human Human Chromosomes Human Engineering Human Genome Image Individual Infertility Kinetochores Location Lysine Malignant Neoplasms Maps Measures Mediating Methods Molecular Neoplasms Normal Cell Outcome Outcome Study Patients Recovery Replication Origin Reporting Research Proposals Role Satellite DNA Site System Testing Validation Variant Work Yeasts base cancer cell cancer genome centromere protein A chromosome movement chromothripsis experimental study functional plasticity patient population

项目摘要

Centromeres are essential to genome inheritance, serving as the site of kinetochore assembly and coordinating chromosome segregation during cell division. Abnormal centromere function is associated with birth defects, infertility, and cancer. Most human centromeres are consistently formed at regions containing highly repetitive alpha satellite DNA. However, in cancer cells, new, ectopic centromeres (neocentromeres) frequently arise on intact chromosomes or small supernumerary marker chromosomes (sSMCs) at genomic regions that lack alpha satellite DNA. Studies in model organisms (Drosophila, yeast, chicken cells) have suggested that certain regions of the genome, including pericentromeres, heterochromatin, and regions of open chromatin or high transcription, are particularly amenable to neocentromere activation. Little is known about the mechanisms of human neocentromere formation or the role of neocentromeres in neoplasia. This is largely due to the lack of experimental systems to study ectopic centromere formation in human cells. In this proposal, we propose to establish CRISPR-based assays to induce neocentromeres on specific human chromosomes, compare their (epi)genomic organization and functional efficiency, and define DNA and chromatin features at sites of formation. In Aim 1, we will use CRISPR-based approaches to independently trigger neocentromere formation on individual human chromosomes after removal or suppression of the native centromere. Our rationale is that by removing or incapacitating the largest concentration of CENP-A, neocentromeres will arise at ectopic sites that harbor low concentrations of CENP-A and/or are vulnerable to CENP-A invasion. In Aim 2, we will define the functional consequences of neocentromere formation by mapping chromatin structure at ectopic centromere regions and measuring the effect of neocentromere formation on gene expression and the surrounding chromatin environment. The technological and intellectual outcomes of this study will fundamentally transform our ability to create and study human chromosome abnormalities and expand our view of genome function and plasticity. Our proposed experiments will establish new methods to induce ectopic centromere assembly on specific human chromosomes to better understand the clinical consequences of neocentromere formation.

着丝粒是基因组遗传的重要组成部分，是着丝粒组装和协调的场所

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A genetic memory initiates the epigenetic loop necessary to preserve centromere position.

遗传记忆启动了维护中心粒位置所需的表观遗传环。

DOI：
10.15252/embj.2020105505
发表时间：
2020-10-15
期刊：
The EMBO journal
影响因子：
0
作者：
Hoffmann S;Izquierdo HM;Gamba R;Chardon F;Dumont M;Keizer V;Hervé S;McNulty SM;Sullivan BA;Manel N;Fachinetti D
通讯作者：
Fachinetti D