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规格是骨骼肌发生的核心。在此过程中，祖肌细胞的基因组被修改，以确保在不表达的基因与需要或将需要表达的基因之间形成稳定的（如果不是不可逆的）区别。 MyoD 是肌肉特异性基因表达所需的转录激活剂。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）中的表达将它们的命运转向骨骼肌表型。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 招募染色质和组蛋白修饰酶。特定但未分化的肌肉前体的规范和维持是基因激活和抑制之间良好平衡的结果。在终末分化细胞中表达的基因在肌肉前体细胞中受到积极抑制。 Ezh2 是赋予多梳抑制复合物 2 (PRC2) 甲基转移酶活性的亚基，它占据并甲基化位于肌肉前体细胞中未表达的肌肉特异性基因调节区域的组蛋白。一旦发生分化，Ezh2 结合就会丢失，组蛋白甲基化也会被消除，从而导致转录激活。除了甲基化-去甲基化之外，其他组蛋白修饰也与肌肉基因表达相关。乙酰化和脱乙酰化处于动态平衡，我们的研究已经确定了几种组蛋白脱乙酰酶 (HDAC) 在控制肌肉分化中的作用。我们使用小分子来调节骨骼肌细胞中几种 HDAC 的酶活性。研究发现，HDAC 的药理调节可改善小鼠营养不良肌肉的形态和功能。为了更好地理解生理和病理条件下基因表达的调节机制，我们将继续鉴定和功能表征引起组蛋白和染色质修饰以及调节骨骼肌细胞增殖、分化和再生的分子。