Epigenetic regulation of transcriptional programming

项目总结 高等生物的基因组由特定的染色体蛋白质和 沿着活性基因、调节元件或静止区的组蛋白修饰。此注释是 对于正确的细胞类型规范至关重要，一个持续的挑战是破译 建立和维护染色质组织。我的实验室专注于染色质的分析 基于其在发育和疾病中的核心重要性的监管复合体，耐人寻味 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 精确的蛋白质相互作用。历史上，我们在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的能力，用于指定细胞类型的关键调控决定。我们的 目前的研究主要集中在多梳群(PcG)蛋白上，由于其高度保守 关键的调控系统我们很容易在苍蝇胚胎和人类胚胎干细胞之间移动。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的早期都处于普遍的“稳定”状态 通过占据多梳抑制复合体1的复合蛋白复合体和 经典的协同激活剂。这些‘二价’蛋白质复合体可以分解成完全激活或 抑制，取决于细胞类型特定的表达、结合和转录功能 各种因素。我们推测转录因子可能以相对杂乱的方式结合，但仍然执行 精确的调控决策，当它们影响这些区域的局部乙酰化/去乙酰化状态时 预先确定的地点。我们的推测模型基于强有力的蛋白质组学证据 与经典的共激活子dBRD4和dMOZ/Morf强相互作用，在染色质上捕获 在果蝇中的胚胎发生，以及CBX7，RING2(PRC1亚单位)， 和BRD1(MoZ/Morf的一个亚单位)。我们相信，我们正处于 在机械学水平上理解染色质转换和转录编程的关键。 这些研究也与我们对异常染色质复合体的分子解剖有协同作用 会导致人类癌症。

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.