Ribonucleoprotein Biogenesis and Epigenetic Gene Regulation

核糖核蛋白生物发生和表观遗传基因调控

• 批准号: 10363745
• 负责人: A. Gregory Matera
• 金额: $ 65.23万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363745
• 关键词: Address; Alleles; Amino Acids; Animal Model; Animals; Binding; Biochemistry; Biogenesis; Biological Models; Biological Process; Cells; Chromatin; Chromosomes; Development; Drosophila melanogaster; Epigenetic Process; Eukaryota; Foundations; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genome; Histones; Housekeeping; Human; Individual; Laboratories; Malignant Neoplasms; Messenger RNA; Missense Mutation; Modeling; Molecular; Molecular Genetics; Motor Neurons; Multigene Family; Mutation; Neuromuscular Diseases; Pathway interactions; Patients; Play; Post-Translational Protein Processing; Process; RNA Processing; Research; Ribonucleoproteins; Role; Series; Small Nuclear Ribonucleoproteins; Spinal Muscular Atrophy; Techniques; Time; Tissues; Transcript; Work; genome-wide; innovation; insight; interest; mutant; neuromuscular; survival motor neuron gene; transmission process

Abstract The research in our laboratory centers on foundational mechanisms that regulate eukaryotic gene expression. In particular, we are interested in roles played by small nuclear ribonucleoproteins (RNPs) and histone post- translational modifications (PTMs) in the transmission of genetic and epigenetic information required for proper metazoan development and genome function. We have developed innovative model systems in Drosophila melanogaster to study gene regulation and neuromuscular disease. Critically, these models allow direct interrogation of specific residues present within conserved genes and multi-gene families. For example, we can now study the biological function of a specific histone PTM by changing the acceptor residue to an amino acid that cannot be appropriately modified and then replacing all wild-type copies of a given histone gene with mutant copies. This approach is not possible in other animal models. Hence, for the first time in any multicellular eukaryote, we can now directly determine the extent to which a given histone PTM contributes to cell fate and organismal development. Similarly, we generated an allelic series of animals that express missense mutations in the Survival Motor Neuron (SMN) gene that are derived from human Spinal Muscular Atrophy (SMA) patients. This series represents the largest number of SMA-causing point mutants currently available in any model organism. Several of these alleles serve as separation-of-function mutations that uncouple the putative housekeeping and tissue-specific activities of SMN, enabling us to study these processes independently. We employ genome-wide techniques together with molecular genetics and biochemistry to identify cellular pathways and binding partners that are dysregulated in human cancer and neuromuscular disease. Using these two powerful genetic platforms, we expect to identify factors and mechanisms that enable a specific chromatin mark to modulate the expression of an individual transcript or an entire chromosome, as well as those that carry out the assembly and maturation of spliceosomal and messenger RNPs.

抽象的 我们实验室的研究重点是调节真核基因表达的基本机制。 我们特别对小核核糖核蛋白（RNP）和组蛋白后发挥的作用感兴趣。 正确传递所需的遗传和表观遗传信息的翻译修饰（PTM） 后生动物发育和基因组功能。我们开发了果蝇创新模型系统 黑腹果蝇研究基因调控和神经肌肉疾病。至关重要的是，这些模型允许直接 询问保守基因和多基因家族中存在的特定残基。例如，我们可以 现在通过将受体残基更改为氨基酸来研究特定组蛋白 PTM 的生物学功能 无法进行适当修改，然后用突变体替换给定组蛋白基因的所有野生型副本 副本。这种方法在其他动物模型中是不可能的。因此，在任何多细胞生物中，这是第一次 对于真核生物，我们现在可以直接确定给定组蛋白 PTM 对细胞命运的贡献程度， 有机体的发育。同样，我们生成了一系列表达错义突变的等位基因动物 存在于源自人类脊髓性肌萎缩症 (SMA) 患者的运动神经元生存 (SMN) 基因中。 该系列代表了目前所有模型中数量最多的 SMA 致病点突变体 生物。其中一些等位基因充当功能分离突变，将假定的 SMN 的内务管理和组织特异性活动，使我们能够独立研究这些过程。我们 采用全基因组技术以及分子遗传学和生物化学来识别细胞途径 以及在人类癌症和神经肌肉疾病中失调的结合伙伴。使用这两个 强大的遗传平台，我们期望识别出实现特定染色质标记的因素和机制 调节单个转录本或整个染色体的表达，以及那些执行 剪接体和信使 RNP 的组装和成熟。