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.

项目摘要 高等生物的基因组被特定的染色体蛋白高度注释， 组蛋白修饰沿着活性基因、调控元件或沉默区。这个注解是 对于正确的细胞类型规范至关重要，并且正在进行的挑战是破译 建立和维持染色质组织。我的实验室主要研究染色质的分析 调节复合物，基于其在发育和疾病中的核心重要性， 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 蛋白质相互作用的精确度。从历史上看，我们为以下方面做出了重大贡献： 了解染色质结构域的靶向和扩散，目前我们正在探索 染色质因子平衡基因以决定细胞类型的关键调控决定的能力。我们 目前的研究集中在Polycomb组（PcG）蛋白，由于其高度保守性， 关键调控系统，我们可以轻松地在苍蝇胚胎和人类胚胎干细胞之间转移。我们 正在开发一种模型，在这种模型中，关键的调控基因在发育早期普遍处于“平衡状态”， 通过多梳抑制复合物1（PRC 1）的复合蛋白复合物的占据， 经典的助活化剂。这些“二价”蛋白质复合物可以分解成完全激活或完全激活。 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，转录因子可能结合相对混杂，但仍然执行 精确的监管决定，当它们影响这些地方的乙酰化/脱乙酰化状态时， 预定的地点。我们的推测模型是基于强有力的蛋白质组学证据， 与经典的共激活剂dBRD 4和dMOZ/MORF强烈相互作用，在染色质上捕获， 果蝇的胚胎发生，并通过CBX 7，RING 2（PRC 1的亚基）， 和BRD 1（MOZ/MORF的亚基）。我们相信， 在机械水平上理解染色质转换和转录编程的尖端。 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， 导致人类癌症