Molecular mechanisms of histone signaling in a chromatin relevant context

染色质相关环境中组蛋白信号传导的分子机制

基本信息

批准号：
9986385
负责人：
Catherine Anne Musselman
金额：
$ 38.2万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9986385
关键词：
Address Autoimmune Diseases Binding Biochemistry Biology Cardiovascular Diseases Cell Nucleus Cells Chromatin Chromatin Structure Complex Cues DNA DNA Sequence Development Epigenetic Process Etiology Fluorescence Spectroscopy Gene Expression Regulation Genetic Transcription Genome Health Histones Human Development Human Genome Human Pathology Instruction Interferometry Malignant Neoplasms Mediating Mental disorders Modification Molecular NMR Spectroscopy Nucleosomes Polycomb Post-Translational Protein Processing Process Proteins Reader Regulation Research Signal Transduction Specificity Structure Thermodynamics X-Ray Crystallography chromatin remodeling developmental disease genetic information histone modification human disease insight interdisciplinary approach model building nervous system disorder programs response targeted treatment

项目摘要

Project Summary The human genome exists in the cell nucleus as chromatin, a complex of the DNA with histone proteins. Though genetic information is encoded in the DNA sequence, another layer of information, is encoded in the histone proteins, specifically in the form of post-translational modifications (PTMs). This layer of information is often referred to as epigenetics, and provides instructions on how the genome is to be regulated. Chromatin and the epigenetic content, is highly dynamic, constantly restructuring in response to developmental and environmental cues. One of the most important questions in biology is how this information is interpreted by transcriptional and other regulatory complexes, leading to gene regulation and cell fate. Histone modifications are “read” through small subdomains within the regulatory complexes called reader domains, and specificity for a unique modification state is thought to be achieved through the integrated activity of multiples of these domains. However, though much is known about the association of reader domains with fragments of histones, the molecular mechanims underlying how they associate with histones in a chromatin relevent context, or how they function together to readout a specific histone modification state, are not well understood. This research program addresses this fundamental question in chromatin regulation. We are pioneering the use of NMR spectroscopy to study the association of reader domains with the basic unit of chromatin, the nucleosome. We are combining this with X-ray crystallography, fluorescence spectroscopy, biolayer interferometry, and basic biochemistry for an overall multidisciplinary approach to building models of these complexes. Over the next five years we will determine the thermodynamic and structural basis of association of reader domains from the BAF chromatin remodeling and Polycomb histone modifying complexes with nucleosomes, the influence of adjacent chromatin binding domains, and the functional consequence of these interactions. Long-term, we will build towards an understand of how multiple reader domains in these complexes integrate to allow these regulatory complexes to navigate and respond to a dynamic chromatin substrate. The results of these studies will reveal fundamental mechanisms of chromatin regulation, provide insight into the etiology of a number of human diseases, and lay the groundwork for the development of targeted therapeutics.

项目摘要人基因组作为染色质存在于细胞核中，这是与组蛋白的DNA的复合物。尽管遗传信息是在DNA序列中编码的，但是在 Hisstone蛋白，特别是以翻译后修饰（PTM）的形式。这层的信息是通常称为表观遗传学，并提供有关如何调节基因组的说明。染色质并且表观遗传含量是高度动态的，不断响应发展和环境提示。生物学中最重要的问题之一是如何解释此信息转录和其他调节复合物，导致基因调节和细胞命运。组蛋白修饰通过称为读取器领域的调节络合物中的小子域“读取”，以及人们认为，通过这些倍数的综合活动来实现独特的修改状态域。但是，尽管对读者领域与组蛋白片段的关联知之甚少，但它们在染色质关系环境中如何与组蛋白相关的分子机制，或它们共同发挥作用以读取特定的组蛋白修饰状态，尚不清楚。这项研究计划在染色质调节中解决了这个基本问题。我们正在开创NMR的使用光谱学研究了读取物结构域与染色质基本单位的核小体的关联。我们将其与X射线晶体学，荧光光谱，Biolayer干扰和基本结合在一起生物化学用于建立这些复合物模型的总体多学科方法。在接下来的五个几年我们将确定BAF读取器域关联的热力学和结构基础染色质重塑和多孔Hisstone与核小体修饰复合物，相邻的影响染色质结合结构域，以及这些相互作用的功能后果。长期，我们将建立要了解这些复合物中的多个读者领域如何整合以允许这些调节复合物导航并响应动态染色质底物。这些研究的结果将揭示染色质调节的基本机制，提供了许多人类的病因疾病，为靶向治疗的发展奠定了基础。