Regulation of gene expression by chromatin remodeling enzymes

染色质重塑酶对基因表达的调节

基本信息

批准号：
10376358
负责人：
ANTHONY N IMBALZANO
金额：
$ 42.04万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376358
关键词：
Address Adult Binding Cell Cycle Regulation Cell Lineage Cell physiology Cells Chromatin Chromatin Structure Derivation procedure Development Embryo Embryonic Development Enzymes Exhibits Family member Gene Activation Gene Expression Gene Expression Regulation Gene Order Gene Structure Genetic Transcription Genome Genomic DNA Growth Hypertrophy In Vitro Maintenance Mediating Methods Modeling Molecular Muscle Muscle Development Myoblasts Myopathy Normal Cell Nucleosomes Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Process Proliferating Rhabdomyosarcoma Role Signal Pathway Signaling Molecule Structure Study models Tissue Differentiation Tissue-Specific Gene Expression Tumor Promoters Tumor Suppressor Proteins Work chromatin remodeling in vivo inhibitor muscle regeneration programs skeletal muscle differentiation transcription factor tumor

项目摘要

PROJECT SUMMARY To understand normal development and differentiation, it is necessary to determine the mechanisms by which cells initiate new programs of gene expression and promote the formation of specific cell lineages. Typically, this involves activation of genes that are transcriptionally silent and that are likely incorporated into repressive chromatin structure. Evidence supports the idea that differentiation-specific transcriptional regulators and enzymes that remodel or alter chromatin structure cooperate to render genomic DNA more accessible to the transcriptional machinery. The mammalian SWI/SNF (mSWI/SNF) enzyme family members remodel nucleosome structure in an ATP dependent manner and facilitate transcription factor function in vitro and in vivo. Components of these enzymes are essential for embryonic development and some can act as tumor suppressors or tumor promoters. Additionally, SWI/SNF enzymes are implicated in cell cycle control. Thus these enzymes are broadly required for normal cell function and for differentiation and development, and their misregulation is implicated in tumor formation. Skeletal muscle differentiation has long been a model for studying fundamental principles of tissue-specific gene expression and differentiation. The SWI/SNF chromatin remodeling enzymes play essential roles in these processes. This project will focus on the mechanisms by which different kinases and phosphatases involved in signaling pathways regulate the phosphorylation and function of SWI/SNF chromatin remodeling enzyme subunits in proliferating and differentiating myoblasts. We will employ methods to manipulate the expression of specific kinases, phosphatases and remodeling enzyme subunits and will manipulate function through use of inhibitors and mutagenensis. We will analyaze the effects of such approaches on gene expression, chromatin binding and remodeling, transcription factor function, local higher-order gene structure, and overall genome organization. The work will provide new paradigms for understanding how signaling molecules converge on chromatin to regulate tissue differentiation and development.

项目概要为了了解正常的发育和分化，有必要确定发育和分化的机制。细胞启动新的基因表达程序并促进特定细胞谱系的形成。通常，这涉及到转录沉默的基因的激活，这些基因可能被纳入抑制性基因中。染色质结构。有证据支持这一观点：分化特异性转录调节因子和重塑或改变染色质结构的酶协同作用，使基因组 DNA 更容易被转录机器。哺乳动物SWI/SNF (mSWI/SNF)酶家族成员重塑以 ATP 依赖性方式构建核小体并促进体外和体内转录因子功能体内。这些酶的成分对于胚胎发育至关重要，其中一些可以充当肿瘤抑制剂或肿瘤促进剂。此外，SWI/SNF 酶还参与细胞周期控制。因此这些酶是正常细胞功能以及分化和发育所广泛需要的，它们的作用失调与肿瘤形成有关。骨骼肌分化长期以来一直是研究组织特异性基本原理的模型基因表达和分化。 SWI/SNF 染色质重塑酶在这些过程。该项目将重点研究不同激酶和磷酸酶的机制参与信号通路调节 SWI/SNF 染色质重塑的磷酸化和功能成肌细胞增殖和分化中的酶亚基。我们将采用方法来操纵特定激酶、磷酸酶和重塑酶亚基的表达，并将操纵功能通过使用抑制剂和诱变剂。我们将分析这些方法对基因的影响表达、染色质结合和重塑、转录因子功能、局部高阶基因结构、和整体基因组组织。这项工作将为理解信号如何传递提供新的范例分子聚集在染色质上以调节组织分化和发育。