Chemical Genomics Paradigm for Epigentic Regulation

表观遗传调控的化学基因组学范式

基本信息

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
项目类别：
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

项目摘要

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）：人类基因组对生理和环境刺激的响应的基因表达取决于DNA和DNA包装组蛋白的化学修饰以及转录因子。这个高度复杂的生物系统以大量和不同的表观遗传修饰组合运行，这使我们完全研究了使用现有工具对其基本机制的完整研究。一个主要的例子是干细胞的生物学，其中自我更新和分化之间的平衡位于其染色质结构如何制定不同的转录程序以指导多能细胞行为的核心。 Yamanaka使用四个转录因子OCT3/4，SOX2，KLF4和C-MYC（OSKM）重新编程了体细胞以诱导多能干细胞，从而突出了基因转录对细胞命运的最终控制。但是，有关OSKM因子如何改变细胞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其自身表达方式的问题尚未得到回答。表观遗传修饰的功能效应是通过表观遗传组读取器（例如乙酰赖氨酸结合溴化群）和甲基赖氨酸结合染色体域的结合来实现的，这些溴化群和甲基 - 赖氨酸结合符号构中存在于转录和染色质调节剂中。与RNA干扰或基因基因敲除不同的是要去除整个蛋白质以及其所有相互作用，小分子抑制剂（化学探针）可以以内源性形式中的多域蛋白质中的单个相互作用去除单一相互作用，从而为复杂生物学系统的时间触发提供了更优质的工具。在这个多学科研究项目中，我们将针对在干细胞生物学中发挥作用的选定的溴结构域和染色体组的高亲和力和选择性化学探针，无论是单独的（即单目标探针）还是在生物学途径中作为一组（即多目标探针）。我们的研究使用具有多学科专业知识的主要研究人员开发的一组连贯的结构/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读取器知识库，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特定目标：（1）基于其表观遗传学功能的表观基因组读取器的目标分析；（2）使用目标结构引导策略进行探测；（3）在干细胞生物学中基因转录调控功能上下文中的探针验证。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。