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Molecular regulation of muscle development by Smyd1

Smyd1 对肌肉发育的分子调节

基本信息

批准号：
10238091
负责人：
Shaojun Du
金额：
$ 32.97万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-07 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238091
关键词：
Address Binding Biochemical Biological Biological Models Birth Cardiac Muscle Contraction Cardiomyopathies Cell Differentiation process Cell Nucleus Cessation of life Complex Cytoplasm Cytosol Data Embryo Exhibits Gene Expression Genes Genetic Genetic Transcription Goals Growth and Development function Heat shock proteins Histone Deacetylase Human In Vitro Knock-out Lysine Mediating Methylation Modeling Molecular Molecular Chaperones Movement Mus Muscle Muscle Cells Muscle Contraction Muscle Development Muscle Fibers Muscle Proteins Muscle function Muscular Atrophy Muscular Dystrophies Mutant Strains Mice Mutate Myoblasts Myocardium Myofibrillogenesis Myofibrils Myopathy Myosin ATPase Nuclear Paralysed Perinatal mortality demographics Phenotype Play Process Protein Methylation Proteins Proteomics Regulation Right ventricular structure Role SET Domain Sarcomeres Skeletal Muscle Structure Testing Transcriptional Regulation Work Zebrafish design histone methylation histone methyltransferase histone modification improved malformation myogenesis new therapeutic target novel novel diagnostics protein degradation protein folding transcription factor

项目摘要

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.

Smyd 1对肌肉发育的分子调控项目摘要该项目的目标是阐明Smyd 1b控制肌肉功能的分子机制细胞分化肌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肌原纤维的规则阵列。骨骼肌和心肌中有缺陷的肌原纤维组装导致肌营养不良、肌肉萎缩和心肌病肌原纤维组装（肌原纤维发生）的分子调控尚不清楚，但最近的研究表明，Smyd 1是一种新的组蛋白甲基转移酶，分化和肌原纤维组装。斑马鱼中Smyd 1b（Smyd 1直向同源物）的缺失导致完全的肌节组织破坏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标志。有趣的是，有趣的是，Smyd 1b在肌细胞分化过程中从细胞核易位到细胞质。而 Smyd 1b在细胞核中作为组蛋白甲基转移酶，与肌球蛋白及其伴侣蛋白Hsp 90 β 1结合，细胞质我们假设Smyd 1b具有双重调节功能。在细胞核中，Smyd 1b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， Smyd 1b在赖氨酸处甲基化肌肉蛋白，并控制蛋白质折叠、稳定性和组装成肌节为了验证这一假设，我们将1）鉴定Smyd 1b靶基因，并确定Smyd 1b靶基因的分子结构。 Smyd 1b调控基因表达的机制; 2）确定功能意义 Smyd 1b在肌原纤维发生中的核质易位功能; 3）鉴定肌肉蛋白在赖氨酸残基上被Smyd 1b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我们将使用强大的斑马鱼模型系统，它允许使用遗传，生物化学和蛋白质组学的方法来解决这些问题。更好地理解机制 Smyd 1b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，这些研究可能会确定新的诊断和治疗目标，治疗肌肉萎缩症和肌病。