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

基本信息

批准号：
10618921
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
项目类别：
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/10618921
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 Deficiency Diseases 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 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 Proliferating Proliferation Marker Property Proteins Regulation Role Skeletal Muscle Specific qualifier value Study models Techniques Testing Time Tissue Differentiation Tissue-Specific Gene Expression Tissues Trace Elements Trace metal Transcriptional Regulation Western Blotting absorption cofactor expectation experimental study genomic locus in vivo iron absorption knock-down mouse model myogenesis novel posttranscriptional prevent programs promoter recruit satellite cell skeletal muscle differentiation transcription factor transcriptome sequencing

项目摘要

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定机制，细胞启动程序基因表达。在正常情况下，谱系测定涉及激活的基因通过特定的转录因子，染色质远方，共激活因子和其他谱系在转录上保持沉默特定分子。骨骼肌分化是研究的绝佳模型组织特异性基因表达和分化，因为对机制有重大理解控制肌源特异性基因表达。但是，新兴的证据显示了一个新颖的类别铜（CU）结合因素可能在调节中具有先前未鉴定的直接影响肌细胞增殖和分化。 Cu是一种必需的痕量金属，可作为多种酶促反应的催化co因子那在生活中扮演关键的角色。 CU缺乏和超负荷会导致病理生理状况 Menkes和Wilson的疾病，中性rop虫，滥用铁受损，周围神经病，线粒体缺乏症和肥厚性心肌病。因此，Cu分布和使用的机制不同的组织和器官以及由于铜的失调而引起的后果对人类健康。有关CU和CU结合因素及其机制的信息有限在肌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节，并取决于铜和铜结合转录因子。我们提出的综合研究结合了潜水者的分子，生化和光谱技术来表征新型分子机制，通过这种机制来调节Cu结合因子肌源分化。我们提出了一个新型模型，其中Cu通过激活Cu-TF来控制肌发生可以同时行动，可以同时行动，或者通过在分化的不同阶段，或两者兼而有之。我们的实验将确定新组件和机制哺乳动物Cu结合因子在谱系特异性基因表达调节中。我们的研究也将建立一个理解与异常CU生物学相关的肌肉疾病的基础 Menkes和Wilson疾病的鼠标模型。了解驱动谱系的分子机制取决于CU的特定基因表达将大大提高我们对几种与CU相关疾病的了解。