Molecular regulation of muscle development by Smyd1

Smyd1对肌肉发育的分子调控 项目摘要 这个项目的目标是阐明Smyd1b控制肌肉的分子机制。 细胞分化。肌肉细胞分化是一个复杂的过程，依赖于协调基因。 肌原纤维蛋白的表达和组装成支持肌肉收缩的规则的肌原纤维阵列。 骨骼肌和心肌中肌原纤维组装缺陷会导致肌营养不良、肌肉萎缩和 心肌病。肌原纤维组装(肌原纤维形成)的分子调控还不是很清楚，但是 最近的研究表明，Smyd1是一种新的组蛋白甲基转移酶，在肌肉细胞中起着关键作用 分化和肌原纤维组装。斑马鱼中Smyd1b(Smyd1同源基因)的缺失导致完整的 肌节组织紊乱和肌肉蛋白质降解增加，导致瘫痪和缺乏 心肌收缩。这些表型是肌病和肌肉萎缩的特征。有趣的是， 有趣的是，Smyd1b在肌肉细胞分化过程中从细胞核转移到细胞质。鉴于 它在细胞核中扮演组蛋白甲基转移酶的角色，Smyd1b与肌球蛋白及其伴侣Hsp901结合。 细胞质。我们假设Smyd1b具有双重调节功能。在细胞核中，Smyd1b调节 通过组蛋白甲基化和与其他转录调节因子相互作用的基因表达。在细胞质中， Smyd1b使肌肉蛋白质在赖氨酸上甲基化，并控制蛋白质的折叠、稳定性和组装成 肉尾蛇。为了验证这一假设，我们将1)识别Smyd1b靶基因并定义分子 Smyd1b调控基因表达的机制；2)确定功能意义 肌原纤维形成中核浆转位到Smyd1b功能的研究；3)鉴定肌肉蛋白质 在赖氨酸残基上被Smyd1b甲基化，并确定赖氨酸甲基化的功能意义 关于肌原纤维形成的。我们将使用强大的斑马鱼模型系统，它允许使用基因， 生物化学和蛋白质组学方法来解决这些问题。对机制有更好的理解 Smyd1b在肌肉细胞中的功能将揭示赖氨酸甲基化在肌肉细胞分化中的作用 和肌原纤维组装。此外，这些研究可能确定新的诊断和治疗靶点 肌营养不良症和肌病的治疗。

Title: Molecular regulation of muscle development by Smyd1 Project Summary The goal of this project is to elucidate the molecular mechanisms by which Smyd1b functions to control muscle cell differentiation. Muscle cell differentiation is a complex process that depends on the coordinated gene expression and assembly of myofibrillar proteins into regular arrays of myofibrils that support muscle contraction. Defective myofibril assembly in skeletal and cardiac muscles leads to muscular dystrophy, muscle atrophy, and cardiomyopathy. The molecular regulation of myofibril assembly (myofibrillogenesis) is not well understood, but recent studies have demonstrated that Smyd1, a novel histone methyltransferase, plays a key role in muscle cell differentiation and myofibril assembly. Loss of Smyd1b (a Smyd1 orthologue) in zebrafish results in complete disruption of sarcomere organization and increased muscle protein degradation, causing paralysis and lack of cardiac muscle contraction. These phenotypes are hallmarks of myopathy and muscle atrophy. Intriguingly, Interestingly, Smyd1b translocates from the nucleus to the cytoplasm during muscle cell differentiation. Whereas it acts as a histone methyltransferase in the nucleus, Smyd1b binds to myosin and its chaperone, Hsp901, in the cytoplasm. We hypothesize that Smyd1b has dual regulatory functions. In the nucleus, Smyd1b regulates gene expression via histone methylation and interacting with other transcriptional regulators. In the cytoplasm, Smyd1b methylates muscle proteins at lysines and control protein folding, stability, and assembly into sarcomeres. To test this hypothesis, we will 1) identify Smyd1b target genes and define the molecular mechanisms by which Smyd1b functions in regulating gene expression; 2) determine the functional significance of nucleus-to-cytoplasm translocation to Smyd1b function in myofibrillogenesis; and 3) identify muscle proteins that are methylated at lysine residues by Smyd1b and determine the functional significance of lysine methylation on myofibrillogenesis. We will use the powerful zebrafish model system, which permits the use of genetic, biochemical, and proteomic approaches, to address these questions. A better understanding of the mechanisms by which Smyd1b functions in muscle cells will unravel the role of lysine methylation in muscle cell differentiation and myofibril assembly. Moreover, these studies may identify new diagnostic and therapeutic targets for treatment of muscular dystrophy and myopathy.