Ribonucleoprotein Biogenesis and Epigenetic Gene Regulation

摘要 我们实验室的研究集中在调控真核基因表达的基本机制上。 特别是，我们对小核核糖核蛋白(RNPs)和组蛋白后蛋白所起的作用感兴趣。 翻译修饰(PTM)在遗传和表观遗传信息传递中的作用 后生动物发育和基因组功能。我们在果蝇身上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 对保守基因和多基因家族中存在的特定残基的询问。例如，我们可以 现在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 不能被适当地修改，然后用突变体替换给定组蛋白基因的所有野生型拷贝 复印件。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第一次 ，我们现在可以直接确定一个给定的组蛋白PTM对细胞命运和 生物体发育。同样，我们产生了一系列表达错义突变的等位基因。 在来自人类脊髓肌萎缩症(SMA)患者的存活运动神经元(SMN)基因中。 这一系列代表了目前所有模型中可用的最大数量的SMA致病点突变 有机体。这些等位基因中有几个是功能分离突变，使假定的 SMN的内务和组织特异性活动，使我们能够独立研究这些过程。我们 将全基因组技术与分子遗传学和生物化学相结合来识别细胞途径 以及在人类癌症和神经肌肉疾病中调节失调的结合伙伴。使用这两个 强大的遗传平台，我们希望确定使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RNPs的组装和成熟。

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.