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

• 批准号: 8157141
• 负责人: Vittorio Sartorelli
• 金额: $ 83.4万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 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/8157141
• 关键词: Modification; Regulation; myogenesis

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 b expressed from 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) redirect 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 is 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 histone 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特化是骨骼肌发生的核心。在这个过程中，祖细胞的基因组被修改，以确保稳定的-如果不是不可逆的-基因之间的区别是不B表达的基因，其表达是或将是必需的。MyoD是肌肉特异性基因表达所需的转录激活因子。外源性MyoD在许多终末分化细胞谱系（神经元、脂肪细胞、皮肤细胞、软骨细胞等）中的表达将其命运重定向至骨骼肌表型。此外，MyoD -和相关的Myf-5蛋白-对于动物骨骼肌的形成至关重要。为了调节转录，MyoD募集染色质和组蛋白修饰酶。指定和维护的承诺，但未分化，肌肉前体是基因激活和抑制之间的良好平衡的结果。在终末分化细胞中表达的基因在肌肉前体中被积极抑制。Ezh 2是赋予多梳抑制复合物2（PRC 2）甲基转移酶活性的亚基，其占据并甲基化位于肌肉前体中不表达的肌肉特异性基因的调节区域的组蛋白。一旦分化终止，Ezh 2结合丧失，组蛋白甲基化被清除，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相关。乙酰化和去乙酰化处于动态平衡，我们的研究已经确定了几种组蛋白去乙酰化酶（HDAC）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的药理学调节可改善小鼠营养不良肌肉的形态和功能。为了更好地理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并调节骨骼肌细胞增殖，分化和再生的分子。