Chromatin Assembly Structure and Function

染色质组装结构和功能

• 批准号: 7864485
• 负责人: Jessica K Tyler
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864485
• 关键词: 26S proteasome; Binding; Biochemistry; Chromatin; Chromatin Assembly and Disassembly; Chromatin Disassembly; Chromatin Modeling; Chromatin Structure; Code; Coupled; DNA; Data; Defect; Disease; Epigenetic Process; Excision; Gene Expression; Genetic Transcription; Genome; Goals; Growth and Development function; Histone Acetylation; Histone Deacetylation; Histone H3; Histones; In Vitro; Inherited; Maintenance; Malignant Neoplasms; Mediating; Modification; Molecular; Molecular Chaperones; Molecular Genetics; Molecular Structure; Nature; Nucleosome Core Particle; Nucleosomes; Positioning Attribute; Process; Promoter Regions; Proteins; Public Health; Regulation; Repression; Research; Research Personnel; Role; Saccharomycetales; Site; Structural Biochemistry; Structure; Therapeutic Intervention; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Ubiquitinated Protein Degradation; Work; chromatin remodeling; gene repression; genetic analysis; histone modification; human disease; in vivo; multicatalytic endopeptidase complex; novel; prevent; programs; promoter; repaired; research study; transcription factor

DESCRIPTION (provided by applicant): The packaging of the eukaryotic genome together with histone proteins into chromatin has profound implications for all processes that occur on the DMA template, including replication, transcription and repair. Chromatin assembly and disassembly are essential for duplication of the genome, yet are poorly understood. Recent studies (including our own) have discovered that chromatin assembly and disassembly, independent of genome duplication, are novel and important means of transcriptional regulation. The long-term goal of this project is to generate a unified understanding of how chromatin disassembly and reassembly regulate transcription. We have uncovered a novel precursor of chromatin disassembly where a transcriptional activator is bound near the dyad axis of symmetry of a nucleosome in vivo, prior to nucleosome disassembly. Our first goal therefore is to identify the chromatin changes that enable activators to destabilize a nucleosome enough to drive chromatin disassembly. Our second goal is to discover the fundamental molecular mechanisms whereby promoter chromatin disassembly and reassembly are essential for transcriptional activation and repression, respectively. The proposed research will also discern whether the ultimate target of histone modifications is to regulate chromatin disassembly and reassembly, and may identify the epigenetic mark that is sufficient to maintain a naked DNA state through replication. Our third goal is to characterize the novel role that we have discovered for the proteasome in chromatin disassembly. By continuing to use molecular genetic analyses focusing on the well-characterized budding yeast PH05 promoter coupled with biochemistry and structural approaches, we are uniquely positioned to fill critical gaps in the current understanding of the fundamental regulation and inheritance of transcription programs. The highly conserved nature of transcriptional regulation mechanisms across eukaryotic species indicates that our findings will be directly applicable to the analysis of human diseases, including many forms of cancer that involve defects in chromatin-utilizing processes. Relevance to the public health. Many diseases are the result of incorrect gene expression. The mechanistic understanding of chromatin assembly and disassembly that will come from this work will further our ability to modify the epigenetic codes involved in human diseases for the purpose of therapeutic intervention.

描述（由申请人提供）：真核基因组以及组蛋白蛋白与染色质的包装对DMA模板上发生的所有过程具有深远的影响，包括复制，转录和修复。染色质组装和拆卸对于重复基因组是必不可少的，但对基因组的重复却很少。最近的研究（包括我们自己的）发现，与基因组重复无关的染色质组装和拆卸是转录调节的新颖而重要的手段。该项目的长期目标是对染色质分解和重新组装如何调节转录产生统一的了解。我们发现了一个新颖的染色质拆卸前体，其中转录激活因子在体内的核小体对称性的对称性轴附近结合，然后在核小体拆卸之前。因此，我们的第一个目标是确定染色质变化，使激活剂能够破坏足以驱动染色质拆卸的核体稳定。我们的第二个目标是发现启动子染色质拆卸和重新组装的基本分子机制，分别对于转录激活和抑制至关重要。拟议的研究还将辨别组蛋白修饰的最终靶标是否是调节染色质拆分和重新组装，并且可以鉴定出足以通过复制来维持赤裸的DNA状态的表观遗传标记。我们的第三个目标是表征我们在染色质分解中发现的蛋白酶体的新颖作用。通过继续使用分子遗传分析，重点是良好的发芽酵母PH05启动子以及生物化学和结构方法，我们在当前对转录程序的基本调节和继承的理解时，我们可以独特地填补关键空白。跨真核物种的转录调节机制的高度保守性质表明，我们的发现将直接适用于人类疾病的分析，包括许多形式的癌症，涉及染色质利润过程中的缺陷。与公共卫生有关。许多疾病是基因表达不正确的结果。从这项工作中，对染色质组装和拆卸的机理理解将进一步进一步改变与治疗干预有关人类疾病的表观遗传代码的能力。