Epigenetic regulation of transcriptional programming

转录编程的表观遗传调控

• 批准号: 10155516
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155516
• 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

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.

项目概要 高等生物的基因组由特定的染色体蛋白高度注释， 沿活性基因、调控元件或沉默区域的组蛋白修饰。这个注释是 对于正确的细胞类型规范至关重要，而持续的挑战是破译细胞类型的规则 建立并维持染色质组织。我的实验室专注于染色质分析 调节复合物，基于它们在发育和疾病中的核心重要性，有趣的 我们最近的研究提出的假设，以及我们使用新方法探测染色质的能力 蛋白质相互作用精确。历史上，我们做出了重大贡献 了解染色质结构域的靶向和传播，目前我们正在探索 染色质因子为特定细胞类型的关键调控决策调整基因的能力。我们的 目前的研究重点是多梳族（PcG）蛋白，并且由于该蛋白的高度保守性 我们在果蝇胚胎和人类胚胎干细胞之间轻松移动的关键调节系统。我们 正在开发一种模型，其中关键调控基因在发育早期普遍“准备就绪” 通过占据多梳抑制复合物 1 (PRC1) 的复合蛋白复合物和 经典共激活剂。这些“二价”蛋白质复合物可能会分解为完全激活或 抑制，取决于细胞类型特异性表达、结合和转录功能 因素。我们推测转录因子可能相对混杂地结合，但仍然执行 精确的监管决策，当它们影响这些地方的局部乙酰化/脱乙酰化状态时 预定站点。我们的推测模型基于强有力的蛋白质组学证据，即 PRC1 与经典共激活剂 dBRD4 和 dMOZ/MORF 强烈相互作用，在染色质上捕获 果蝇的胚胎发生，以及通过 CBX7、RING2（PRC1 的亚基）的类似共占用， 和人胚胎干细胞中的 BRD1（MOZ/MORF 的一个亚基）。我们相信我们正处于 从机械层面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相协同 导致人类癌症。