Chemical Genomics Paradigm for Epigenetic Regulation

表观遗传调控的化学基因组学范式

• 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
• 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

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基因和基因产物中编码的信息转化为对它们在细胞生理和病原体生理学中的功能的理解，并将其转化为新的医学方法。但是，我们目前的知识仅限于对遗传信息的调节和转导，这些信息被认为是受基因组DNA序列中未编码的可遗传信息所支配的 - 表观遗传学的本质。我们研究的长期目标是为人类基因组的表观遗传调节的基因组规模研究开发创新的工具和技术。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（即胞嘧啶的甲基化）和染色体DNA包装组蛋白的化学修饰（即乙酰化，乙酰化，甲基化，磷酸化和泛液化）决定了。统一的模型已经出现，提出了嵌入染色质中的“表观遗传密码”，该模型表示诸如异染色质形成或转录激活等不同核活动的区域。该神秘代码是通过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来解释。在组蛋白中“读取”乙酰赖氨酸的甲基-CPG结合结构域的发现，甲基赖氨酸的染色体或PHD手指为这种工作假设提供了支持证据。为了了解控制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研究与表观遗传调节有关的生理条件下染色体蛋白的研究。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，用于基于结构的小分子探针的组蛋白结合蛋白的功能设计。这种范式依赖于结构和化学生物学的一系列实验和计算方法，以及分子/细胞染色质生物学，这些生物学是在关注该系统研究的关键研究人员之间开发的。作为新的范式夫妻配体设计在表观遗传控制中染色体蛋白的全基因组功能分析，我们称其为化学表观基因组学。我们预计，这项研究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指导基因沉默或激活的调节能力。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。化学探针基于结构的功能设计 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：人类基因组的遗传信息的调节和转导，尽管有接近完整的基因组序列信息，但我们当前的知识受到限制，它不仅受DNA序列中编码的信息，而且还受表观遗传信息，而且还受到DNA复杂化学修饰的遗传性遗传信息，以及染色体DNA的复杂化学修饰。在这个项目中，我们建议开发创新的工具和技术，这些工具和技术是在基因组规模上产生极大的关于结构功能和染色体蛋白机制的新知识，以及在基因组尺度上的机制，以及开发新型的选择性小分子化学探针的方法，以促进其在其内生蛋白质中的生物学作用，以促进其在其内生蛋白质中，以探测其内生蛋白的质量，以探测其内生的质量，以使其在其内生成量的生物学功能，以供染色体质量促进染色体的染色体质量，以探测其内生的生物学作用。一种新的基因组学研究范式，我们称化学表观基因组学。我们预计，对组蛋白定向染色质生物学的化学表观基因组学研究的新出现的推论对进一步的研究具有广泛的影响，这些研究从对基本人类表观遗传学，干细胞认同和命运到新的表观遗传疗法的新发展到人类疾病的新发展范围。