Mechanisms of Cu-binding factors to promote myogenic gene expression

项目总结 细胞的发育和分化需要特定的细胞启动程序的机制 关于基因表达的。在正常情况下，血统决定涉及到激活 特定转录因子、染色质重构体、共激活子和其他谱系的转录沉默 特定的分子。骨骼肌分化是研究骨骼肌分化基本原理的极佳模型。 由于对组织特异性基因表达和分化机制有重要的了解 控制生肌特异性基因的表达。然而，新出现的证据表明，一种新的类别 铜(铜)的结合因素可能会在调节中产生以前未被认识到的直接影响 成肌细胞的增殖和分化。 铜是一种必需的痕量金属，可作为多种酶反应的催化辅因子。 在生活中扮演关键角色的人。铜缺乏和超负荷会导致病理生理状况，包括 门克斯和威尔逊病，中性粒细胞减少，铁吸收受损，周围神经病变，线粒体 缺乏症和肥厚型心肌病。因此，铜在土壤中的分布和利用机制 不同的组织和器官，以及铜摄取失调造成的后果，对 人类健康。有关铜和铜结合因子及其机制的信息有限。 在肌肉发生和大多数发育过程中的作用。我们建议阐明基因的新机制。 驱动肌肉分化和发育的调控以及依赖于铜和铜结合的调控 转录因子。我们建议进行综合研究，结合不同的分子、生化和 用光谱技术表征铜结合因子调控的新分子机制 肌源性分化。我们提出了一种新的模型，其中铜通过激活铜-转铁蛋白来控制肌肉发生 可以通过同时作用于不同的启动者或通过在 分化的不同阶段，或者两者都有。我们的实验将确定新的组件和机制 哺乳动物铜结合因子对谱系特异性基因表达的调节。我们的研究也将 为了解与铜生物异常相关的肌肉疾病奠定基础 孟克斯和威尔逊病的小鼠模型。了解驱动血统的分子机制 依赖于铜的特异性基因表达将极大地促进我们对几种铜相关疾病的认识。

PROJECT SUMMARY Cell development and differentiation require lineage specific mechanisms by which cells initiate programs of gene expression. In normal conditions, lineage determination involves activation of genes that are transcriptionally silent by specific transcription factors, chromatin remodelers, coactivators, and other lineage specific molecules. Skeletal muscle differentiation is an excellent model for studying fundamental principles of tissue-specific gene expression and differentiation as there is a significant understanding of mechanisms controlling myogenic-specific gene expression. However, emerging evidence shows a novel category of Copper (Cu)-binding factors that may have a previously unappreciated direct impact in the regulation of myoblast proliferation and differentiation. Cu is an essential trace metal that serves as a catalytic co-factor for a wide variety of enzymatic reactions that play critical roles in life. Cu deficiency and overload leads to pathophysiological conditions including Menkes and Wilson’s diseases, neutropenia, impaired iron absorption, peripheral neuropathy, mitochondrial deficiencies and hypertrophic cardiomyopathy. Therefore, the mechanisms for Cu distribution and usage in different tissues and organs, as well as the consequences due to dysregulated Cu acquisition, are important to human health. Limited information is available regarding Cu and Cu-binding factors and their mechanisms of action in myogenesis and most developmental processes. We propose to elucidate novel mechanisms of gene regulation that drive muscle differentiation and development and that are dependent on copper and Cu-binding transcription factors. We propose integrative studies that combine diverse molecular, biochemical and spectroscopic techniques to characterize novel molecular mechanisms by which Cu-binding factors regulate myogenic differentiation. We propose a novel model where Cu controls myogenesis by activating Cu-TFs that may act synchronously, either by acting on different promoters at the same time or by acting sequentially at different stages of differentiation, or both. Our experiments will identify new components and mechanisms for mammalian Cu-binding factors in the regulation of lineage-specific gene expression. Our studies also will establish a basis for understanding muscular diseases related to aberrant Cu biology using well-characterized mouse models for Menkes and Wilson’s diseases. Understanding the molecular mechanisms that drive lineage specific gene expression dependent on Cu will greatly advance our knowledge of several Cu-related diseases.