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Control of Myogenesis and Regulation of MyoD Post-Transcriptional Modifications

肌生成的控制和 MyoD 转录后修饰的调节

基本信息

批准号：
9359791
负责人：
Vittorio Sartorelli
金额：
$ 130.92万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9359791
关键词：
Acetylation Adipocytes Animal Model Animals Area Binding Cell Lineage Cells Chondrocytes Chromatin Chromatin Structure Complex Deacetylation Development Ensure Enzymes Equilibrium Gene Activation Gene Expression Genes Genetic Transcription Genome Goals Histones In Vitro Intervention Knock-in Mouse Knock-out Maintenance Methylation Methyltransferase Modification Molecular Morphology Mus Muscle Muscle Cells Muscle Fibers Muscular Dystrophies Myogenin Natural regeneration Neurons Nucleic Acid Regulatory Sequences Phenotype Physiological Polycomb Process Proteins Recruitment Activity Regulation Research Role Skeletal Muscle Skin Totipotent Stem Cells Transcription Coactivator Transcriptional Activation Transgenic Organisms Undifferentiated chromatin modification chromatin remodeling demethylation gene repression histone methylation histone modification interest muscle regeneration myogenesis progenitor repaired skeletal small molecule tissue culture

项目摘要

The specification of skeletal muscle cells, starting from totipotent stem cells, lies at the core of skeletal myogenesis. During this process, the genome of the progenitor muscle cells is modified to ensure that stable - if not irreversible - distinctions are made between genes not to be expressed and genes whose expression is or will be required. MyoD is a transcriptional activator required for muscle-specific gene expression. Expression of exogenous MyoD in numerous terminally differentiated cell lineages (neurons, adipocytes, skin cells, chondrocytes and others) redirects their fates towards the skeletal muscle phenotype. Furthermore, MyoD - and the related Myf-5 protein - is essential for the formation of skeletal muscles in the animal. In order to regulate transcription, MyoD recruits chromatin and histone modifying enzymes. Specification and maintenance of committed, yet undifferentiated, muscle precursors are the result of a fine balance between gene activation and repression. Genes to be expressed in terminally differentiated cells are actively repressed in muscle precursors. Ezh2, the subunit conferring methyltransferase activity to the Polycomb Repressive Complex 2 (PRC2), occupies and methylates histones located at regulatory regions of muscle-specific genes not expressed in muscle precursors. Once differentation ensues, Ezh2 binding is lost and histone methylation is erased, resulting in transcriptional activation. In addition to methylation-demethylation, other histone modifications are associated with muscle gene expression. Acetylation and deacetylation are in a dynamic equilibrium, and our studies have identified a role for several histone deacetylases (HDACs) in controlling muscle differentiation. We have used small molecules to modulate the enzymatic activity of several HDACs in skeletal muscle cells. Pharmacological modulation of the HDACs was found to ameliorate the morphology and function of mouse dystrophic muscles. With the aim of contributing to a better understanding of the mechanisms that regulate gene expression in physiological and pathological conditions, we will continue to identify and functionally characterize molecules that cause histone and chromatin modifications and regulate proliferation, differentiation, and regeneration of skeletal muscle cells.

从全能干细胞开始的骨骼肌细胞的规范是骨骼肌发生的核心。在这个过程中，前体肌肉细胞的基因组被修改，以确保不表达的基因和需要表达的基因之间存在稳定的--如果不是不可逆转的--区别。MyoD是肌肉特异性基因表达所必需的转录激活剂。外源性MyoD在许多终末分化细胞系(神经元、脂肪细胞、皮肤细胞、软骨细胞和其他)中的表达将它们的命运重新定向到骨骼肌表型。此外，MyoD和相关的Myf-5蛋白对动物骨骼肌的形成是必不可少的。为了调节转录，MyoD招募染色质和组蛋白修饰酶。确定和维持承诺的，但未分化的肌肉前体是基因激活和抑制之间微妙平衡的结果。在终末分化细胞中表达的基因在肌肉前体细胞中受到积极抑制。EZH2是多梳抑制复合体2(PRC2)的甲基转移酶活性的亚基，它占据并甲基化位于肌肉前体中未表达的肌肉特异基因的调节区的组蛋白。一旦发生分化，Ezh2结合就会丢失，组蛋白甲基化也会被清除，从而导致转录激活。除了甲基化-去甲基化，其他组蛋白修饰与肌肉基因表达有关。乙酰化和脱乙酰化是一种动态平衡，我们的研究已经确定了几种组蛋白脱乙酰酶(HDACs)在控制肌肉分化中的作用。我们已经使用小分子来调节骨骼肌细胞中几种HDAC的酶活性。发现HDAC的药理调节可以改善小鼠营养不良肌肉的形态和功能。为了更好地了解在生理和病理条件下调节基因表达的机制，我们将继续鉴定和功能表征引起组蛋白和染色质修饰的分子，并调控骨骼肌细胞的增殖、分化和再生。