Epigenetic regulation of transcriptional programming

转录编程的表观遗传调控

• 批准号: 10398124
• 负责人: Mitzi I Kuroda
• 金额: $ 71.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398124
• 关键词: Acetylation; Binding; Cells; Chromatin; Complex; Deacetylation; Development; Disease; Dissection; Drosophila genus; Embryo; Embryonic Development; Genes; Genetic Transcription; Genome; Human; Laboratories; Malignant Neoplasms; Mediating; Modeling; Molecular; Organism; PRC1 Protein; Polycomb; Post-Translational Protein Processing; Proteins; Proteomics; Regulator Genes; Regulatory Element; Repression; Site; Specific qualifier value; System; Time; Transcriptional Regulation; base; cell type; chromatin protein; epigenetic regulation; fly; histone modification; human embryonic stem cell; novel strategies; protein complex; protein protein interaction; transcription factor; Acetylation; Binding; Cells; Chromatin; Complex; Deacetylation; Development; Disease; Dissection; Drosophila genus; Embryo; Embryonic Development; Genes; Genetic Transcription; Genome; Human; Laboratories; Malignant Neoplasms; Mediating; Modeling; Molecular; Organism; PRC1 Protein; Polycomb; Post-Translational Protein Processing; Proteins; Proteomics; Regulator Genes; Regulatory Element; Repression; Site; Specific qualifier value; System; Time; Transcriptional Regulation; base; cell type; chromatin protein; epigenetic regulation; fly; histone modification; human embryonic stem cell; novel strategies; protein complex; protein protein interaction; transcription factor

PROJECT SUMMARY The genomes of higher organisms are highly annotated by specific chromosomal proteins and histone modifications along active genes, regulatory elements, or silent regions. This annotation is critical for proper cell type specification, and an ongoing challenge is to decipher the rules that establish and maintain chromatin organization. My laboratory focuses on analysis of chromatin regulatory complexes, based on their central importance in development and disease, the intriguing hypotheses raised by our recent studies, and our ability to use new approaches to probe chromatin protein interactions with precision. Historically, we have made significant contributions to understanding the targeting and spreading of chromatin domains, and currently we are probing the ability of chromatin factors to poise genes for key regulatory decisions that specify cell type. Our current studies focus on the Polycomb group (PcG) proteins, and due to the high conservation of this key regulatory system we move between fly embryos and human embryonic stem cells with ease. We are developing a model in which key regulatory genes are universally ‘poised’ early in development via occupancy of composite protein complexes of Polycomb Repressive Complex 1 (PRC1) and classical co-activators. These ‘bivalent’ protein complexes may resolve into full activation or repression, depending on the cell type-specific expression, binding, and function of transcription factors. We speculate that transcription factors may bind relatively promiscuously, but still execute precise regulatory decisions, when they influence the local acetylation/deacetylation state at these predetermined sites. Our speculative model is based on strong proteomic evidence that PRC1 strongly interacts with classic co-activators, dBRD4 and dMOZ/MORF, captured on chromatin during embryogenesis in Drosophila, and by analogous co-occupancy of CBX7, RING2 (subunits of PRC1), and BRD1 (a subunit of MOZ/MORF) in human embryonic stem cells. We believe that we are on the cusp of understanding chromatin transitions and transcriptional programming at a mechanistic level. These studies also synergize with our molecular dissection of aberrant chromatin complexes that drive human cancers.

项目摘要 较高生物体的基因组由特定的染色体蛋白和 沿活动基因，调节元素或无声区域的组蛋白修饰。该注释是 对于适当的单元类型规范至关重要，而持续的挑战是破译规则 建立和维护染色质组织。我的实验室专注于染色质的分析 监管复合物基于其在发育和疾病中的核心重要性，有趣 我们最近的研究提出的假设以及使用新方法探测染色质的能力 蛋白质相互作用与精度相互作用。从历史上看，我们为 了解染色质域的靶向和扩散，目前我们正在探测 染色质因子能够为指定细胞类型的关键调节决策固定基因。我们的 当前的研究重点是Polycomb组（PCG）蛋白，并且由于对此有很高的保护 关键调节系统我们轻松地在蝇胚和人类胚胎干细胞之间移动。我们 正在开发一个模型，其中关键的监管基因在开发初期普遍“有利” 通过占用Polycomb抑制复合物1（PRC1）的复合蛋白复合物和 古典共同激活剂。这些“二动”蛋白络合物可能会完全激活或 抑制，取决于细胞类型特异性的表达，转录的结合和功能 因素。我们推测转录因子可能会相对滥交，但仍执行 精确调节决策，当它们影响局部乙酰化/脱乙酰化状态时 预定位点。我们的投机模型基于强有力的蛋白质组学证据表明PRC1 与经典的共激活因子DBRD4和DMOZ/MORF强烈相互作用，在染色质上捕获 果蝇中的胚胎发生，并通过CBX7，RING2（PRC1的亚基）的类似同居 和人类胚胎干细胞中的BRD1（MOZ/MORF的亚基）。我们相信我们正在 理解染色质转变和转录编程的尖端。 这些研究还与我们对异常染色质复合物的分子解剖协同作用 推动人类癌症。