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：
10456324
负责人：
Teresita Del Nino Jesus Padilla-Benavides
金额：
$ 35.78万
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/10456324
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

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.

项目概要细胞发育和分化需要细胞启动程序的谱系特定机制在正常情况下，谱系决定涉及基因的激活。特定转录因子、染色质重塑因子、共激活因子和其他谱系导致转录沉默骨骼肌分化是研究基本原理的绝佳模型。组织特异性基因表达和分化，因为对机制有深入的了解然而，新出现的证据显示了一种新的类别。铜 (Cu) 结合因子可能对调节产生先前未被认识到的直接影响成肌细胞增殖和分化。 Cu 是一种重要的微量金属，可作为多种酶反应的催化辅助因子铜缺乏和超载会导致病理生理状况，包括门克斯和威尔逊病、中性粒细胞减少症、铁吸收受损、周围神经病变、线粒体因此，铜的分布和使用机制。不同的组织和器官，以及铜获取失调造成的后果，对于关于铜和铜结合因子及其机制的信息有限。我们建议阐明基因的新机制。驱动肌肉分化和发育并依赖于铜和铜结合的调节我们提出结合不同分子、生化和转录因子的综合研究。光谱技术表征铜结合因子调节的新分子机制我们提出了一种新的模型，其中铜通过激活铜转录因子来控制肌生成。可以通过同时作用于不同的启动子或通过在我们的实验将确定分化的不同阶段或两者的新成分和机制。我们的研究还将研究哺乳动物铜结合因子对谱系特异性基因表达的调节。使用充分表征的方法为理解与异常铜生物学相关的肌肉疾病奠定基础门克斯病和威尔逊病的小鼠模型了解驱动谱系的分子机制。依赖于铜的特定基因表达将极大地增进我们对几种铜相关疾病的认识。