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Genetic and Epigenetic Determinants of Centromere Identity

着丝粒身份的遗传和表观遗传决定因素

基本信息

批准号：
10726950
负责人：
BARBARA MELLONE
金额：
$ 1.81万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
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：
2019-08-01 至 2025-05-31
项目状态：
未结题

项目摘要

Project Summary Centromeres are essential chromosomal elements that mediate kinetochore assembly and accurate chromosome segregation. Centromere defects lead to chromosome missegregation, with detrimental effects on cell and organism health and fertility. In most multicellular species, centromeres are composed of large regions of highly repetitive DNA marked by chromatin containing the centromere-specific histone variant CENP-A. Previous work demonstrated that both centromeric DNA and CENP-A chromatin have the potential to initiate centromere activity de novo; however, their respective contributions to centromere specification in mitosis and meiosis have remained elusive. The overall goal of this proposal is to determine how centromeric DNA and chromatin contribute to centromere identity. The centromeres of metazoans have been refractory to full sequencing and assembly due their large size and highly repetitive nature, hampering our ability to systematically interrogate the role of centromeric DNA elements. Additionally, there are currently no systems in which to test if de novo centromeres, which are devoid of centromeric DNA, and can sustain centromere function and specification through mitotic and meiotic divisions. Using our unique advancements in Drosophila, which include the identification and assembly of its centromeric sequences and the establishment of an inducible de novo centromere system, this proposal will: 1) test if chromatin-mediated centromeres can sustain chromosome segregation through development and meiosis, effectively replacing endogenous centromeres; 2) test specific hypothesis on how centromeric DNA elements may contribute to CENP-A chromatin establishment or maintenance. Collectively, this work will shed light into centromere specification mechanisms in Drosophila, an exceptional model system that allows centromere studies in the context of animal development and fertility- with broad relevance to other species, including humans.

项目概要着丝粒是介导着丝粒组装和精确定位的重要染色体元件。染色体分离。着丝粒缺陷导致染色体错误分离，产生有害影响关于细胞和有机体的健康和生育能力。在大多数多细胞物种中，着丝粒由大的由含有着丝粒特异性组蛋白变体的染色质标记的高度重复的 DNA 区域 CENP-A。先前的工作表明，着丝粒 DNA 和 CENP-A 染色质都有可能从头开始着丝粒活动；然而，它们各自对着丝粒规范的贡献有丝分裂和减数分裂仍然难以捉摸。该提案的总体目标是确定着丝粒如何 DNA 和染色质有助于着丝粒的识别。后生动物的着丝粒难以抵抗完整的测序和组装由于其体积大和高度重复的性质，阻碍了我们的能力系统地探究着丝粒 DNA 元件的作用。此外，目前还没有系统用于测试缺乏着丝粒 DNA 的从头着丝粒是否可以维持着丝粒通过有丝分裂和减数分裂来实现功能和规格。利用我们在果蝇方面的独特进步，其中包括其着丝粒序列的鉴定和组装以及建立诱导型从头着丝粒系统，该提案将：1）测试染色质介导的着丝粒是否能够维持通过发育和减数分裂进行染色体分离，有效取代内源着丝粒； 2）测试有关着丝粒 DNA 元件如何促进 CENP-A 染色质建立的具体假设或维护。总的来说，这项工作将揭示果蝇的着丝粒规范机制，一个特殊的模型系统，可以在动物发育和生育能力的背景下进行着丝粒研究- 与包括人类在内的其他物种具有广泛的相关性。