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: 10588149
• 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/10588149
• 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; Gene Expression; Gene Expression Regulation; 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; Spliceosomes; Techniques; Time; Tissues; Transcript; Work; gene conservation; genome-wide; innovation; insight; interest; messenger ribonucleoprotein; model organism; 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.

摘要 我们实验室的研究集中在调节真核基因表达的基础机制上。 特别是，我们感兴趣的小核核糖核蛋白（RNP）和组蛋白后， 翻译修饰（PTM）在传递遗传和表观遗传信息所需的适当 后生动物发育和基因组功能。我们在果蝇中开发了创新的模型系统 研究基因调控和神经肌肉疾病。关键是，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。比如我们可以 现在，我通过将受体残基改变为氨基酸来研究特定组蛋白PTM的生物学功能 然后用突变体替换给定组蛋白基因的所有野生型拷贝 份这种方法在其他动物模型中是不可能的。因此，这是第一次在任何多细胞 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， 有机体发育同样，我们产生了一系列表达错义突变的动物的等位基因， 在源自人类脊髓性肌萎缩症（SMA）患者的运动神经元存活（SMN）基因中。 这一系列代表了最大数量的SMA引起的点突变体目前可在任何模式 有机体这些等位基因中有几个作为功能分离突变， SMN的管家和组织特异性活动，使我们能够独立研究这些过程。我们 利用全基因组技术结合分子遗传学和生物化学来识别细胞通路 以及在人类癌症和神经肌肉疾病中失调的结合伴侣。使用这两 强大的遗传平台，我们希望能够确定使特定的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。