Regulation of Differentiation Gene Expression by MyoD

MyoD 对分化基因表达的调控

• 批准号: 7093347
• 负责人: ASOKE K MAL
• 金额: $ 27.19万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093347
• 关键词: amidohydrolases; cell differentiation; cell growth regulation; cell line; cell proliferation; chromatin; epigenetics; functional /structural genomics; gene environment interaction; gene induction /repression; genetic promoter element; genetic regulation; histones; human genetic material tag; laboratory mouse; methyltransferase; mitogen activated protein kinase; myoblasts; myogenesis; neoplasm /cancer genetics; protein kinase; protein protein interaction; protein structure function; rhabdomyosarcoma; striated muscles; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Proliferation into differentiation is a hallmark of biological systems that undergo differentiation. Skeletal muscle differentiation has long been a model for studying other differentiation process. The process is initiated by the formation of precursor myoblast cells. Defects in this program is linked to degenerative diseases, muscle loss and muscle tumors. Proliferation into differentiation of myoblasts involves activation of genes that specify muscle. Thus, studying the regulation of differentiation responsible gene expression in this model system will provide insight into other cell-specific differentiation program and its importance in disease. The transcriptional regulator MyoD is essential for myoblasts formation and differentiation. Although MyoD is expressed in myoblasts, it does not activate genes in switching myoblasts to differentiate without the stimulus of differentiation. MyoD function in inducing differentiation is deregulated in rhabdomyosarcoma (RMS). The long-term goal of this application is to identify mechanism that regulates MyoD in the balance between proliferation and differentiation. This proposal will address the role of MyoD in chromatin modification in the regulation of differentiation responsible gene expression. By interacting with histone deacetylase (HDAC), MyoD inhibits muscle gene expression and differentiation. Our preliminary data indicate that histone methyltransferase Suv39h1, which is involved in gene silencing, inhibits MyoD activity. Moreover, forced activation of promyogenic pSSMAPK overcomes this inhibitory effect. In this proposal, we propose the hypotheses that (i) MyoD establishes an epigenetic gene silencing mechanism in myoblast cells to prevent to differentiation, and (ii) Differentiation-dependent stimulus modulates chromatin proceeding myoblast cells to differentiate. We will test these hypotheses by pursuing the following specific aims: (1) to define whether MyoD establishes an epigenetic gene silencing mechanism in myoblast cells to prevent differentiation. (2) To determine whether differentiation-dependent stimulus modulates chromatin proceeding myoblast cells to differentiate. (3) To identify whether the deficiency in differentiation-dependent stimulus sustains muscle genes in silenced chromatin preventing rhabdomyosarcoma (RMS) cells differentiation. It is our expectation that completion of these AIMS will lead to novel therapies for muscle-related diseases.

描述（由申请人提供）：增殖分化是经历分化的生物系统的标志。骨骼肌分化长期以来一直是研究其他分化过程的模型。该过程由前体成肌细胞的形成启动。该程序的缺陷与退行性疾病、肌肉损失和肌肉肿瘤有关。成肌细胞的增殖分化涉及特定肌肉的基因的激活。因此，研究该模型系统中分化相关基因表达的调节将有助于深入了解其他细胞特异性分化程序及其在疾病中的重要性。转录调节因子 MyoD 对于成肌细胞的形成和分化至关重要。尽管MyoD在成肌细胞中表达，但在没有分化刺激的情况下，它不会激活使成肌细胞分化的基因。在横纹肌肉瘤 (RMS) 中，MyoD 诱导分化的功能失调。该应用的长期目标是确定调节 MyoD 增殖和分化之间平衡的机制。该提案将探讨 MyoD 在染色质修饰中在调节分化相关基因表达中的作用。通过与组蛋白脱乙酰酶 (HDAC) 相互作用，MyoD 抑制肌肉基因表达和分化。我们的初步数据表明，参与基因沉默的组蛋白甲基转移酶 Suv39h1 会抑制 MyoD 活性。此外，强制激活早生肌 pSMAPK 可以克服这种抑制作用。在本提案中，我们提出以下假设：(i) MyoD 在成肌细胞中建立表观遗传基因沉默机制以阻止分化，(ii) 分化依赖性刺激调节染色质进行成肌细胞分化。我们将通过追求以下具体目标来检验这些假设：（1）确定MyoD是否在成肌细胞中建立表观遗传基因沉默机制以阻止分化。 (2)确定分化依赖性刺激是否调节染色质进行成肌细胞分化。 (3) 确定分化依赖性刺激的缺乏是否会维持沉默染色质中的肌肉基因，从而阻止横纹肌肉瘤（RMS）细胞分化。我们期望这些目标的完成将为肌肉相关疾病带来新的疗法。