Comprehensive analysis of epigenetic regulators in their native chromatin context

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。一个正在进行的 挑战在于破译建立和维持染色质组织的规则。在即将到来的 在资助期内，我们建议将重点放在聚梳组(PcG)蛋白质的分析上，基于 它们在发育和疾病中的核心重要性，我们目前提出的耐人寻味的假设 结果，以及我们使用新方法精确探测染色质蛋白质相互作用的能力。 我们的研究将集中在多功能果蝇模型上，但由于这一关键的高度保守 监管系统我们可以很容易地在苍蝇和人类系统之间移动。我们的实验将 解决染色质生物学中的两个核心问题：理解靶向和传播 染色质结构域，并探索染色质因子标记基因作为未来调控因子的能力 细胞类型特异性。在目标1中，我们将定义协调的一系列分子相互作用 规范的和变异的PcG复合体。在目标2中，我们将分析H3K27me3是如何在 顺，以创造可遗传的压抑领域。在目标3中，我们将确定一个二价态 启动果蝇的发育基因。我们在学习上的成功将与 了解发育和疾病中正常和异常的基因组组织和功能。

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. An ongoing challenge is to decipher the rules that establish and maintain chromatin organization. In the upcoming funding period, we propose to focus on analysis of the Polycomb group (PcG) proteins, based on their central importance in development and disease, the intriguing hypotheses raised by our current results, and our ability to use new approaches to probe chromatin protein interactions with precision. Our studies will focus on the versatile Drosophila model, but due to the high conservation of this key regulatory system we can move between fly and human systems with ease. Our experiments will address two central problems in chromatin biology: understanding the targeting and spreading of chromatin domains, and probing the ability of chromatin factors to mark genes as future regulators of cell type specificity. In Aim 1, we will define the series of molecular interactions that coordinate canonical and variant PcG complexes. In Aim 2, we will analyze how H3K27me3 is propagated in cis, to create heritable repressive domains. In Aim 3, we will determine whether a bivalent state primes developmental genes in Drosophila. Success in our studies will be highly relevant to understanding normal and aberrant genome organization and function in development and disease.