Regulation of Differentiation Gene Expression by MyoD

MyoD 对分化基因表达的调控

基本信息

批准号：
7792414
负责人：
ASOKE K MAL
金额：
$ 26.85万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-03 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7792414
关键词：
Address Adult Affect Biological Models Cell Differentiation process Cell Line Cells Childhood Rhabdomyosarcoma Chromatin Complex Coupled Data Defect Degenerative Disorder Development Disease Environment Enzymes Epigenetic Process Equilibrium Exercise Failure Gene Activation Gene Expression Gene Silencing Gene Targeting Genes Genetic Transcription Goals Growth HDAC1 gene Histone Deacetylase Histone H3 Human In Vitro Injury Lead Link MAP2K6 gene MAPK14 gene Mediating Mitogens Modeling Molecular Molecular Conformation Mus Muscle Muscle Cells Myoblasts Myogenin Myomatous neoplasm Natural regeneration Pathway interactions Phosphotransferases Play Process Proliferating Proteins RPS6KA5 gene Regulation Rhabdomyosarcoma Role Skeletal Muscle Specific qualifier value Stimulus Stress Study models Testing To specify Work biological systems chromatin modification expectation histone acetyltransferase histone methyltransferase histone modification insight neoplastic cell novel postnatal prevent programs promoter skeletal muscle differentiation

项目摘要

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 modulats 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.

增殖分化是生物系统经历分化的标志。骨骼肌肉分化长期以来一直是研究其他分化过程的模型。过程是由前体成肌细胞的形成引发。该程序中的缺陷与退化有关疾病、肌肉损失和肌肉肿瘤。成肌细胞增殖分化涉及激活特定肌肉的基因。因此，研究分化相关基因表达的调控该模型系统将提供对其他细胞特异性分化程序及其重要性的深入了解疾病。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，但它不会激活成肌细胞分化的基因没有分化的刺激。 MyoD 诱导分化的功能失调横纹肌肉瘤（RMS）。该应用程序的长期目标是确定调节机制 MyoD 处于增殖和分化之间的平衡。该提案将解决 MyoD 的角色染色质修饰在调节分化相关基因表达中的作用。通过互动组蛋白脱乙酰酶 (HDAC)、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 抑制 MyoD 活动。此外，强制激活早生肌 pSMAPK 可以克服这种抑制作用。在这个提案中，我们提出假设：（i）MyoD 在中建立了表观遗传基因沉默机制成肌细胞阻止分化，以及 (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内容来检验这些假设目的：（1）明确MyoD是否在成肌细胞中建立表观遗传基因沉默机制防止分化。 (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) 判断是否存在缺陷分化依赖性刺激维持沉默染色质中的肌肉基因横纹肌肉瘤（RMS）细胞分化。我们期望这些目标的完成将导致肌肉相关疾病的新疗法。