Chemical Genomics Paradigm for Epigentic Regulation

表观遗传调控的化学基因组学范式

• 批准号: 8608445
• 负责人: Ming-Ming Zhou
• 金额: $ 92.74万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608445
• 关键词: Affinity; Binding; Bioinformatics; Biological; Biology; Biomedical Research; Bromodomain; Cell Fate Control; Cells; Chemicals; Chromatin; Chromatin Structure; Communities; DNA; DNA Modification Process; Development; Disease; Embryo; Epigenetic Process; Equilibrium; Excision; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Health; Heart; Histones; Human; Human Biology; Human Genome; Informatics; Interdisciplinary Study; Investigation; Knowledge; Ligands; Link; Lysine; Methodology; Methods; Modification; Molecular; Outcome; PHD Finger; Pathway interactions; Phase; Physiological; Production; Proteins; Publications; RNA Interference; Reader; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Somatic Cell; Stem cells; Stimulus; Structure; Technology; Tertiary Protein Structure; Testing; Transcriptional Regulation; Validation; base; c-myc Genes; cell behavior; cell transformation; cell type; complex biological systems; design; empowered; epigenome; epigenomics; induced pluripotent stem cell; inhibitor/antagonist; insight; knockout gene; knowledge base; multidisciplinary; programs; response; self-renewal; small molecule; small molecule libraries; stem; stem cell biology; three dimensional structure; tool; transcription factor

DESCRIPTION (provided by applicant): Gene expression of the human genome in response to physiological and environmental stimuli is dictated by chemical modifications of the DNA and the DNA-packing histones, as well as transcription factors. This highly complex biological system that operates with a large number and different combinations of epigenetic modifications has defied our full investigation of its basic mechanisms with existing tools. A prime example is the biology of stem cell in which a balance between self-renewal and differentiation lies at the heart of how its chromatin structure enacts different transcriptional programs to instruct pluripotent cell behavior. Yamanaka's reprogramming of somatic cells to induced pluripotent stem cells using four transcription factors Oct3/4, Sox2, Klf4 and c-Myc (OSKM) highlights the ultimate control of cell fate by gene transcription. However, the questions on how the OSKM factors transform the cell's epigenome and how their own expression are controlled during stem cell self-renewal and differentiation are yet to be answered. The functional effects of epigenetic modifications are realized by the binding of epigenome readers such as the acetyl-lysine binding bromodomain and the methyl-lysine binding chromodomain that are present in transcription and chromatin regulators. Unlike RNA interference or gene knockout that entails the removal of an entire protein along with all its interactions, a small-molecule inhibitor (chemical probe) could remove a single interaction in a multi-domain protein in its endogenous form, thus providing a much finer tool for the temporal perturbation of the complex biological system. In this multidisciplinary research project, we will develop high affinity and selective chemical probes for a selected group of bromodomains and chromodomains that function in stem cell biology, either individually (i.e. single-target probes) or as a group in a biological pathway (i.e. multi-target probes). Our study uses a coherent set of structural/chemical biology and chromatin/stem cell biology methods being developed by our key investigators with multidisciplinary expertise. We will also develop an Epigenome Reader KnowledgeBase to aid target profiling, design, production and validation of new chemical probes. To attain these goals, we will achieve the following three specific aims: (1) Target profiling of epigenome readers based on their epigenetic functions; (2) Probe development using target structure-guided strategy; and (3) Probe validation in a functional context of gene transcriptional regulation in stem cell biology.

描述（由申请人提供）：人类基因组响应生理和环境刺激的基因表达由 DNA 和 DNA 包装组蛋白以及转录因子的化学修饰决定。这种高度复杂的生物系统需要大量不同的表观遗传修饰组合，我们无法利用现有工具对其基本机制进行全面研究。一个典型的例子是干细胞生物学，其中自我更新和分化之间的平衡是其染色质结构如何制定不同转录程序来指导多能细胞行为的核心。 Yamanaka 使用四种转录因子 Oct3/4、Sox2、Klf4 和 c-Myc (OSKM) 将体细胞重编程为诱导多能干细胞，凸显了基因转录对细胞命运的最终控制。然而，OSKM因子如何改变细胞的表观基因组以及在干细胞自我更新和分化过程中如何控制它们自身的表达等问题仍有待解答。表观遗传修饰的功能效应是通过表观基因组读取器的结合来实现的，例如存在于转录和染色质调节因子中的乙酰赖氨酸结合溴结构域和甲基赖氨酸结合染色结构域。与需要去除整个蛋白质及其所有相互作用的RNA干扰或基因敲除不同，小分子抑制剂（化学探针）可以去除内源形式的多结构域蛋白质中的单个相互作用，从而为复杂生物系统的时间扰动提供更精细的工具。在这个多学科研究项目中，我们将为在干细胞生物学中发挥作用的一组选定的溴结构域和染色结构域开发高亲和力和选择性的化学探针，无论是单独的（即单靶探针）还是作为生物途径中的一组（即多靶探针）。我们的研究使用了由我们具有多学科专业知识的主要研究人员开发的一套连贯的结构/化学生物学和染色质/干细胞生物学方法。我们还将开发一个表观基因组阅读器知识库，以帮助新化学探针的目标分析、设计、生产和验证。为了实现这些目标，我们将实现以下三个具体目标：（1）根据表观遗传功能对表观基因组读者进行目标分析； (2) 使用目标结构引导策略进行探针开发； (3) 在干细胞生物学基因转录调控的功能背景下进行探针验证。

项目成果

Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains.

• DOI: 10.1021/jm401334s
• 发表时间: 2013-11-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhang G;Plotnikov AN;Rusinova E;Shen T;Morohashi K;Joshua J;Zeng L;Mujtaba S;Ohlmeyer M;Zhou MM
• 通讯作者: Zhou MM

Thermodynamic basis of selectivity in guide-target-mismatched RNA interference.

引导-靶标-错配 RNA 干扰选择性的热力学基础。

• DOI: 10.1002/prot.24025
• 发表时间: 2012-05
• 期刊: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
• 影响因子: 2.9
• 作者: Joseph, Thomas T.;Osman, Roman
• 通讯作者: Osman, Roman