Chemical Genomics Paradigm for Epigenetic Regulation

表观遗传调控的化学基因组学范式

基本信息

批准号：
7943541
负责人：
Ming-Ming Zhou
金额：
$ 59.73万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943541
关键词：
Acetylation Address Affinity Binding Bioinformatics Biological Process Biology Biomedical Research Bromodomain Cell physiology Cells Chemicals Chromatin Code Collaborations Combinatorial Synthesis Complex Computing Methodologies Couples Cytosine DNA Modification Process DNA Sequence Development Emerging Technologies Enzymes Epigenetic Process Family Family Sizes Feedback Gene Activation Gene Expression Regulation Gene Silencing Generations Genes Genetic Transduction Genomics Goals Heterochromatin Histones Human Human Genome Investigation Knowledge Lead Ligands Link Lysine Mammalian Cell Mediating Medicine Methodology Methods Methylation Modeling Modification Molecular Biology Molecular Profiling Mutagenesis Nuclear PCAF gene PHD Finger Phosphorylation Physiological Physiology Polycomb Protein Binding Proteins Reading Regulation Research Research Personnel Site Stem cells Stimulus Structure Structure-Activity Relationship Subgroup System Technology Tertiary Protein Structure Transcriptional Activation Transfection Translating Ubiquitination Work Yeasts base complex biological systems design epigenomics genome sequencing genome-wide histone modification histone-binding proteins human disease improved innovation novel novel strategies public health relevance response scaffold small molecule tool

项目摘要

DESCRIPTION (provided by applicant): The grand challenge in post genomic biomedical research is to translate the information encoded in genes and gene products of the human genome into an understanding of their functions in cellular physiology and patho- physiology, and into new approaches to medicine. However, our current knowledge is limited about the regulation and transduction of the genetic information that is believed to be governed by heritable information not encoded in the genomic DNA sequence - the essence of epigenetics. The long-term goal of our research is to develop innovative tools and technologies for the genomic scale study of epigenetic regulation of the human genome. Recent studies show that gene activation or silencing in response to physiological and environmental stimuli is dictated by chemical modifications of the DNA (i.e. methylation of cytosine) and of the chromosomal DNA-packing histones (i.e. acetylation, methylation, phosphorylation and ubiquitination). A unifying model has emerged to suggest an "epigenetic code" embedded in chromatin that signifies regions of distinct nuclear activities such as heterochromatin formation or transcriptional activation. This enigmatic code is established by chromatin modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of the methyl-CpG binding domain, the bromodomain that "reads" acetyl-lysine in histones, and the chromodomain or the PHD finger for methyl-lysine provides supporting evidence for this working hypothesis. To understand the fundamental principles that govern epigenetic gene regulation, new methodologies and innovative tools are needed for genome-wide investigation of chromosomal proteins in physiological conditions as pertained to the epigenetic regulation. Towards this goal, we propose to develop a new chemical genomics paradigm for structure-based functional design of small-molecule probes for histone binding proteins. This paradigm relies on a coherent set of experimental and computational methods of structural and chemical biology, and molecular/cell chromatin biology that are being developed in collaborations among the key investigators focused on the study of this system. As the new paradigm couples ligand design to genome-wide functional profiling of chromosomal proteins in epigenetic control, we term it Chemical Epigenomics. We expect that the new chemical tools and technologies emerging from this study will help address questions such as how histone modifications lead to regulatory capabilities of the chromatin in directing gene silencing or activation. We aim to attain the following three Specific Aims: 1. Genome-wide profiling of chromosomal protein domains in histone recognition 2. Structure-based functional design of chemical probes 3. Chemical epigenomics study of histone-directed chromatin biology PUBLIC HEALTH RELEVANCE: The regulation and transduction of genetic information of the human genome, of which our current knowledge is limited despite the available near complete genome sequence information, is governed by information not only encoded in the DNA sequence, but also by the epigenetic information that is heritable in the complex chemical modifications of the DNA as well as the chromosomal DNA-packing histones. In this project, we propose to develop innovative tools and technologies that are required for the generation of an extremely large amount of new knowledge on structure-function and mechanisms of chromosomal proteins on the genomic scale, and also the means to develop novel selective small-molecule chemical probes to enable investigation of biological functions of chromosomal proteins in their endogenous forms and under physiological conditions as pertained to the epigenetic gene regulation a new genomics research paradigm we term Chemical Epigenomics. We expect that the emerging inferences on the Chemical Epigenomics study of the histone- directed chromatin biology have broad implications on further investigations that range from new understanding of the fundamental human epigenetics, stem cell identity and fate to the new development of novel epigenetic therapies to human disease.

描述（由申请人提供）：后基因组生物医学研究的巨大挑战是将人类基因组的基因和基因产物中编码的信息转化为对其在细胞生理学和病理生理学中的功能的理解，并转化为新的医学方法。然而，我们目前对遗传信息的调控和转导的了解有限，遗传信息被认为是由未编码在基因组 DNA 序列中的遗传信息（表观遗传学的本质）控制的。我们研究的长期目标是开发创新工具和技术，用于人类基因组表观遗传调控的基因组规模研究。最近的研究表明，响应生理和环境刺激的基因激活或沉默是由 DNA 的化学修饰（即胞嘧啶甲基化）和染色体 DNA 包装组蛋白（即乙酰化、甲基化、磷酸化和泛素化）决定的。一个统一的模型已经出现，表明染色质中嵌入了“表观遗传密码”，该密码表示不同核活动的区域，例如异染色质形成或转录激活。这种神秘的密码是由染色质修饰酶建立的，并由以修饰敏感方式结合染色质的蛋白质解释。甲基-CpG 结合结构域、“读取”组蛋白中乙酰赖氨酸的溴结构域以及甲基赖氨酸的染色结构域或 PHD 指的发现为这一工作假设提供了支持证据。为了了解表观遗传基因调控的基本原理，需要新的方法和创新工具来对生理条件下与表观遗传调控相关的染色体蛋白进行全基因组研究。为了实现这一目标，我们建议开发一种新的化学基因组学范式，用于组蛋白结合蛋白小分子探针的基于结构的功能设计。该范式依赖于结构和化学生物学以及分子/细胞染色质生物学的一套连贯的实验和计算方法，这些方法是在专注于该系统研究的关键研究人员之间的合作中开发的。由于新的范式将配体设计与表观遗传控制中染色体蛋白的全基因组功能分析结合起来，我们将其称为化学表观基因组学。我们期望本研究中出现的新化学工具和技术将有助于解决诸如组蛋白修饰如何导致染色质在指导基因沉默或激活方面的调节能力等问题。我们的目标是实现以下三个具体目标： 1. 组蛋白识别中染色体蛋白结构域的全基因组分析 2. 基于结构的化学探针功能设计 3. 组蛋白定向染色质生物学的化学表观基因组学研究公共卫生相关性：人类基因组遗传信息的调节和转导不仅受到 DNA 序列中编码的信息的控制，而且还受到表观遗传信息的控制，尽管我们目前的知识仍然有限，尽管可以获得接近完整的基因组序列信息DNA 以及染色体 DNA 包装组蛋白的复杂化学修饰是可遗传的。在这个项目中，我们建议开发创新的工具和技术，这些工具和技术是产生大量关于基因组规模上染色体蛋白的结构功能和机制的新知识所必需的，同时也是开发新型选择性小分子的方法。分子化学探针能够研究内源形式和生理条件下染色体蛋白的生物学功能，与表观遗传基因调控有关，这是一种新的基因组学研究范式，我们称之为化学表观基因组学。我们预计，组蛋白定向染色质生物学的化学表观基因组学研究的新推论对进一步的研究具有广泛的影响，这些研究的范围从对基本人类表观遗传学、干细胞身份和命运的新理解到人类新型表观遗传疗法的新发展。疾病。