Mechanisms of Cu-binding factors to promote myogenic gene expression

铜结合因子促进生肌基因表达的机制

• 批准号: 10209843
• 负责人: Teresita Del Nino Jesus Padilla-Benavides
• 金额: $ 36.15万
• 依托单位: WESLEYAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209843
• 关键词: Affect; Ataxia; Binding; Binding Sites; Biochemical; Biochemical Reaction; Biology; Cardiac; Categories; Cell Differentiation process; Cell Lineage; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Cellular Stress; ChIP-seq; Chromatin; Chromatin Structure; Coenzymes; Complex; Copper; Coupled; Culture Media; Data; Development; Developmental Process; Differentiation Antigens; Disease; Dystonia; Enzymes; Excretory function; Failure; Family; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomic DNA; Growth; Growth and Development function; Health; Hepatolenticular Degeneration; Homeostasis; Human; Hydroxyl Radical; Hypertrophic Cardiomyopathy; Immunoprecipitation; Impairment; Ions; Knock-out; Knowledge; Life; Location; Mass Spectrum Analysis; Menkes Kinky Hair Syndrome; Metabolism; Metals; Mitochondria; Modeling; Modification; Molecular; Molecular Chaperones; Mus; Muscle; Muscle Development; Muscle hypotonia; Mutation; Myoblasts; Myogenin; Myopathy; Neurologic; Neutropenia; Organ; Pathologic; Pathology; Patients; Peptide Sequence Determination; Peripheral Nervous System Diseases; Phenotype; Play; Proliferation Marker; Property; Proteins; Regulation; Role; Skeletal Muscle; Study models; Techniques; Testing; Time; Tissue Differentiation; Tissue-Specific Gene Expression; Tissues; Trace Elements; Trace metal; Transcriptional Regulation; Western Blotting; absorption; chromatin remodeling; expectation; experimental study; genomic locus; in vivo; iron absorption; knock-down; mouse model; myogenesis; novel; prevent; programs; promoter; recruit; satellite cell; skeletal muscle differentiation; transcription factor; transcriptome sequencing

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.

项目摘要 细胞发育和分化需要谱系特异性机制，细胞通过这些机制启动程序 的基因表达。在正常情况下，谱系决定涉及基因的激活， 转录沉默的特定转录因子，染色质重塑，共激活因子和其他谱系， 特定分子骨骼肌分化是研究骨骼肌分化的基本原理的极好模型。 组织特异性基因表达和分化，因为对机制有重要的了解 控制成肌特异性基因表达。然而，新出现的证据显示， 铜（Cu）结合因子，可能有一个以前未认识到的直接影响，在调节 成肌细胞增殖和分化。 铜是一种必需的微量金属，作为多种酶促反应的催化辅因子 在生命中扮演着重要角色。铜缺乏和超负荷导致病理生理条件，包括 Menkes和Wilson病，中性粒细胞减少症，铁吸收受损，周围神经病变，线粒体 和肥厚型心肌病。因此，铜在土壤中的分布和利用机制可能与土壤中铜的分布和利用有关。 不同的组织和器官，以及由于铜的获取失调的后果，是重要的， 人体健康有限的信息是关于铜和铜结合因子及其机制， 在肌生成和大多数发育过程中起作用。我们建议阐明新的机制，基因 调节驱动肌肉分化和发育，并依赖于铜和铜结合 转录因子我们建议综合研究，将联合收割机不同的分子，生物化学和 光谱技术来表征铜结合因子调节的新分子机制 肌源性分化我们提出了一种新的模型，其中Cu通过激活Cu-TF来控制肌生成， 可以通过同时作用于不同的启动子或通过依次作用于不同的启动子来同步作用。 不同的分化阶段，或两者。我们的实验将确定新的成分和机制， 哺乳动物铜结合因子在谱系特异性基因表达的调节。我们的研究也将 建立一个基础，了解肌肉疾病有关的异常铜生物学使用良好的表征， Menkes和Wilson病的小鼠模型。了解驱动谱系的分子机制 依赖于铜的特异性基因表达将极大地推进我们对几种铜相关疾病的认识。