Defining the molecular interactions that drive histone locus body formation and function

定义驱动组蛋白位点体形成和功能的分子相互作用

基本信息

  • 批准号:
    10464621
  • 负责人:
  • 金额:
    $ 6.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Eukaryotic nuclei are crowded compartments that not only compact but also organize meters of DNA. This feat is achieved by wrapping DNA around histone proteins to form nucleosomes, the basic units of chromatin. Histone levels in the cell are precisely balanced: a lack of histone expression causes cell cycle arrest, whereas histone overexpression leads to genomic instability. Although histone gene regulation is crucial for proper cell viability and function, mechanisms that regulate histone gene expression are poorly defined. Histone genes are often clustered in metazoan genomes. In the genome of the excellent model system Drosophila melanogaster, a single cluster encompasses all the canonical histone genes. A suite of transcription and processing factors occupy the histone gene locus and form a conserved structure known as the histone locus body (HLB). Mutations in known HLB members lead to defects in HLB formation and/or histone gene expression, often causing animal lethality or infertility. We do not know all the factors that occupy the histone locus and contribute to histone gene regulation, and there are large gaps in our understanding of how HLB factors specifically target the histone gene locus. The overall goal of this proposal is to define the molecular interactions at the histone locus that specify histone genes for unique regulation. Recent studies identified the Drosophila protein CLAMP, which binds specifically to GA-repeat sequences within the histone3/histone4 promoter, opens chromatin across the histone locus, and promotes expression of all histone genes. However, it is unclear if CLAMP is required at the histone locus prior to the localization of HLB-specific factors, which would implicate CLAMP in specifying the locus for HLB formation. In Aim 1, I will define the DNA-protein interactions that lead to HLB formation and histone gene expression. I will take advantage of an established transgenic histone locus system to (A) probe the positional requirements of the CLAMP-GA-repeat interaction and (B) determine the placement of CLAMP in the developmental hierarchy of HLB formation. It is also critical that we define HLB composition, as this is an important step towards defining mechanisms of HLB formation and histone gene regulation. In Aim 2, I will discover novel HLB factors using both an unbiased proteomic screen and a candidate approach that involves mining existing -omics datasets. This candidate approach will also be the basis of a Course-Based Undergraduate Research Experience (CURE) module that I will develop and utilize in both my future independent laboratory and classroom. Collectively, these experiments will define mechanisms of HLB formation and histone gene expression while expanding my experimental repertoire and generating new directions for my future laboratory and classroom.
项目摘要 真核细胞核是拥挤的隔间,不仅紧凑,而且组织DNA的米。 这一壮举是通过将DNA包裹在组蛋白蛋白周围形成核小体(细胞的基本单位)来实现的 染色质细胞中的组蛋白水平是精确平衡的:缺乏组蛋白表达会导致细胞周期停滞, 而组蛋白过表达导致基因组不稳定性。虽然组蛋白基因调控对于 适当的细胞活力和功能,调节组蛋白基因表达的机制还不清楚。 组蛋白基因通常在后生动物基因组中聚集。在优秀模型系统的基因组中 黑腹果蝇,一个单一的集群包括所有的经典组蛋白基因。一套抄写本 和加工因子占据组蛋白基因位点并形成称为组蛋白的保守结构 位点体(HLB)。已知HLB成员的突变导致HLB形成和/或组蛋白基因缺陷 表达,常导致动物死亡或不育。我们并不知道占据组蛋白的所有因子 基因座,并有助于组蛋白基因调控,并且在我们对HLB如何调节的理解中存在很大的差距。 因子特异性地靶向组蛋白基因位点。该提案的总体目标是定义分子 在组蛋白基因座的相互作用,指定组蛋白基因的独特调控。 最近的研究发现了果蝇蛋白CLAMP,其特异性结合GA重复序列 组蛋白3/组蛋白4启动子内的序列,打开组蛋白基因座上的染色质, 所有组蛋白基因的表达。然而,目前尚不清楚CLAMP是否需要在组蛋白基因座之前, HLB特异性因子的定位,这将暗示CLAMP在指定HLB形成的位点。在 目的1:明确DNA-蛋白质相互作用对HLB形成和组蛋白基因表达的影响。我会 利用已建立的转基因组蛋白基因座系统来(A)探测 CLAMP-GA-repeat相互作用和(B)决定CLAMP在发育层次中的位置 HLB的形成。定义HLB组成也很关键,因为这是定义HLB组成的重要一步。 HLB形成和组蛋白基因调控的机制。在目标2中,我将发现新的HLB因子, 无偏的蛋白质组学筛选和涉及挖掘现有组学数据集的候选方法。 这种候选人的方法也将是基于课程的本科生研究经验(CURE)的基础 我将在我未来的独立实验室和课堂上开发和利用这个模块。总的来说,这些 实验将确定HLB形成和组蛋白基因表达的机制,同时扩大我的研究范围。 实验曲目和产生新的方向,为我未来的实验室和教室。

项目成果

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