3D Genome Organization and Gene Expression in Drosophila

果蝇 3D 基因组组织和基因表达

• 批准号: 10314733
• 负责人: Nicole Torosin
• 金额: $ 2.99万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2022-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314733
• 关键词: 3D; Genome; Organization; Gene; Expression

Project Summary/Abstract Topologically associating domains (TADs) are three-dimensional organizational units that bring distant genetic loci into close proximity with their regulatory elements and demarcate regions of highly-interacting chromatin. Early studies suggested that TADs play a critical role in gene regulation since they were found to be highly conserved in verte- brates and Drosophila. However, more recent research suggests that TADs are frequently reorganized and that re- structuring does not affect gene expression. The lack of clarity surrounding both TAD conservation and the role of TADs in regulating gene expression represents a critical barrier to understanding genetic regulatory evolution. The long-term goal within the field of 3D genome evolution is to elucidate the relationship between 3D genome organiza- tion and gene expression. The objective of this proposal is to describe the relationship between 3D genome evolu- tion and gene expression by characterizing the conservation and divergence of TAD structures and gene expression across 11 species of Drosophila. My preliminary data show that the rate of TAD and gene expression evolution may vary by TAD subtype based on chromatin enrichment. Therefore, my central hypothesis is that rate of TAD evolu- tion and the associated divergence in gene expression varies by TAD subtype. I will test this hypothesis through the following specific aims: I will 1) implement a phylogenetic comparative analysis to evaluate the conservation of TAD architecture and accompanying gene expression profiles across 11 Drosophila species and 2) use CRISPR to test the effects of lineage-specific TAD disruptions on 3D genome organization and gene expression directly. The proposed research represents an innovative approach because it will take advantage of natural variation between species of Drosophila to describe the relationship between TADs and gene expression. Disruption of TAD boundaries has been associated with aberrant enhancer-promoter contacts and gene misregulation, leading to developmental abnormalities and cancer . These results will assist in future research identifying genetic factors causing species-specific genetic ex- pression patterns and disease states, and improve overall understanding of the evolution of gene regulation. The training plan focuses on formal education of the applicant in computational genomic and molecular genetic approaches through courses, workshops, and completion of the proposed research in the Sponsor's laboratory setting. The training outlined in this proposal will prepare the applicant to accomplish her career goal of leading a research team studying basic evolutionary processes in wild and model organisms as a multifaceted approach to discover the genetic underpinning of health and disease. The Co-Sponsors for this proposal have the expertise in evolutionary genomics and genetic structural variation, and Rutgers University has the resources, facilities, and intellectual environment to support the applicant through the training period and ensure a successful transition to independence and attainment of her goal.

项目总结/摘要 拓扑关联结构域（TADs）是一种三维组织单位，它将遥远的遗传基因位点整合到一起， 与它们的调节元件紧密接近，并划分高度相互作用的染色质区域。早期研究 表明TADs在基因调控中起着关键作用，因为它们在verte中高度保守， 动物和果蝇。然而，最近的研究表明，TADs经常重组，并且重组 结构化不影响基因表达。缺乏明确的周围都生态保护和作用， TADs在调控基因表达中的作用是理解遗传调控进化的关键障碍。的 3D基因组进化领域的长期目标是阐明3D基因组组织之间的关系， 和基因表达。该建议的目的是描述3D基因组进化与基因组进化之间的关系。 通过表征转录结构和基因表达的保守性和差异性， 在11种果蝇中的应用我的初步数据显示，基因表达和进化的速度可能 根据染色质富集的不同亚型而不同。因此，我的中心假设是， 和相关的基因表达差异因亚型而异。我将通过 以下具体目标：1）实施系统发育比较分析，以评估野生动物的保护 结构和伴随的基因表达谱在11个果蝇物种和2）使用CRISPR来测试 谱系特异性破坏对3D基因组组织和基因表达的直接影响。拟议 研究代表了一种创新的方法，因为它将利用物种之间的自然变异， 果蝇来描述TADs和基因表达之间的关系。边界的破坏已经 与异常的增强子-启动子接触和基因失调相关，导致发育异常 和癌症这些结果将有助于未来的研究，确定导致物种特异性遗传前体的遗传因素。 表达模式和疾病状态，并提高对基因调控进化的整体理解。 培训计划侧重于申请人在计算基因组学和分子遗传学方面的正规教育 通过课程、研讨会和在申办者的实验室环境中完成拟议研究的方法。 本建议书中概述的培训将帮助申请人完成领导研究团队的职业目标 研究野生生物和模式生物的基本进化过程，作为发现基因的多方面方法。 健康和疾病的基础。该提案的共同发起人拥有进化基因组学方面的专业知识 和遗传结构变异，罗格斯大学拥有资源，设施和智力环境， 在培训期间为申请人提供支持，并确保成功过渡到独立， 她的目标。

项目成果

Long-read genome assemblies for the study of chromosome expansion: Drosophila kikkawai, Drosophila takahashii, Drosophila bipectinata, and Drosophila ananassae.

• DOI: 10.1093/g3journal/jkad191
• 发表时间: 2023-09-30
• 期刊: G3 (Bethesda, Md.)
• 作者: Leung W;Torosin N;Cao W;Reed LK;Arrigo C;Elgin SCR;Ellison CE
• 通讯作者: Ellison CE

Long-read genome assemblies for the study of chromosome expansion: Drosophila kikkawai , Drosophila takahashii , Drosophila bipectinata , and Drosophila ananassae.

用于染色体扩展研究的长读基因组组装：Drosophila kikkawai、Drosophila takahashii、Drosophila bipectinata 和 Drosophila ananassae。

• DOI: 10.1101/2023.05.22.541758
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Leung,Wilson;Torosin,Nicole;Cao,Weihuan;Reed,LauraK;Arrigo,Cindy;Elgin,SarahCR;Ellison,ChristopherE
• 通讯作者: Ellison,ChristopherE