Establishment of Active Chromatin Domains

染色质结构域在早期发育过程中在细胞核内形成， 在母体向合子的转变过程中共同调节附近的基因。在合子之前 基因组激活，整个基因组是非常开放的，只有几个关键的早期转录 各种因素都是有限制的。然而，许多基本的活性和抑制性染色质结构域是存在的 合子基因组激活后。关于胚胎是如何快速发育的，人们知之甚少 确定对受精卵功能至关重要的关键活性染色质结构域 基因组。 下面是关于活性染色质结构域的几个关键问题，我们将在本文中解决 建议书： 1)不同的效应复合体是如何针对活性染色质区域的 通过类似的方式 顺式元件，以便在正确的基因组位置形成正确的结构域？ 2)识别相似顺式元件的转录因子之间的竞争如何调节 发育过程中活性染色质结构域的形成？ 3)活性染色质结构域的三维结构是如何建立的？ 有许多重要的染色质结构域在整个过程中协调基因的激活 基因组包括rDNA基因座、组蛋白基因座和剂量补偿男性 X染色体，所有这些都必须在发育中的胚胎中被适当地激活。我的 研究计划最初集中在两个基本的染色质结构域上 协调果蝇基因的激活：1)平衡的剂量补偿的X染色体 性别间的基因剂量与2)协调的组蛋白基因座体(HLb) 调节组蛋白基因的表达。果蝇是研究果蝇的理想生物 染色质结构域在发育早期由于其快速和同步的早期形成 发展以及现有的大量遗传和生化工具和基因组数据集。 虽然已经鉴定了许多调节染色质结构域的顺式和反式作用因子， 对驱动它们在特定基因组座位上形成的分子机制知之甚少 在早期发育过程中。确定活跃雄性的染色质区域是如何 随着发育时间的推移，X染色体和HLB的建立和维持将揭示 活性染色质结构域形成的关键原则。使用稳态测量，我们有 最近发现，一个单一的转录因子，CLAMP，调节两个基因的形成 剂量补偿的X染色体和HLB活性染色质结构域，为我们提供了一个入口 揭示染色质结构域动态过程的新观点 队形。我们工作的意义在于，我们将定义活性染色质区域是如何形成的 并将寻求确定共同的潜在机制，以推动 在特定的基因组座位上形成两个非常不同的结构域。

Chromatin domains form within the nucleus during early development to precisely co-regulate nearby genes during the maternal to zygotic transition. Prior to zygotic genome activation, the entire genome is very open and only a few key early transcription factors are bound. Yet, many essential active and repressive chromatin domains are present right after zygotic genome activation. Little is understood about how embryos rapidly establish the critical active chromatin domains that are essential for the function of the zygotic genome. Here are several key questions about active chromatin domains that we will address in this proposal: 1) How are different effector complexes specifically targeted to active chromatin domains by similar cis-elements such that the proper domain forms at the correct genomic location? 2) How does competition between transcription factors that recognize similar cis-elements regulate the formation of active chromatin domains during development? 3) How is the three-dimensional architecture of active chromatin domains established? There are many essential chromatin domains that mediate coordinate gene activation throughout the genome including the rDNA locus, the histone locus and the dosage compensated male X-chromosome, all of which must be properly activated in the developing embryo. My research program has initially focused on two of these essential chromatin domains of coordinate gene activation in Drosophila: 1) the dosage compensated X-chromosome that balances gene dosage between sexes and 2) the histone locus body (HLB) that coordinately regulates histone gene expression. Drosophila is an ideal organism with which to study the formation of chromatin domains early in development due to their rapid and synchronized early development and the large number of genetic and biochemical tools and genomic data sets available. While many cis and trans acting factors that regulate chromatin domains have been identified, little is known about the molecular mechanisms that drive their formation at specific genomic loci during early development. Defining how the chromatin domains on the active male X-chromosome and the HLB are established and maintained over developmental time will reveal key principles by which active chromatin domains form. Using steady-state measurements, we have recently discovered that a single transcription factor, CLAMP, regulates formation of both the dosage compensated X-chromosome and the HLB active chromatin domains, providing us an entry point for revealing new insights into the dynamic process of chromatin domain formation. The significance of our work is that we will define how active chromatin domains form over developmental time and will seek to identify common underlying mechanisms that drive formation of two very different domains at specific genomic loci.