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Establishment of Active Chromatin Domains

活性染色质结构域的建立

基本信息

批准号：
10373015
负责人：
Erica Nicole Larschan
金额：
$ 39.87万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

项目摘要

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.

染色质结构域在早期发育过程中在细胞核内形成，在母体到合子的转变过程中共同调节附近的基因。合子前基因组激活，整个基因组是非常开放的，只有几个关键的早期转录因素是有约束力的。然而，许多重要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。关于胚胎如何迅速地建立对合子功能至关重要的关键活性染色质结构域基因组以下是我们将在本节中讨论的关于活性染色质结构域的几个关键问题。建议： 1)不同的效应复合物是如何特异性靶向活性染色质结构域的通过类似顺式元件，使适当的结构域形成在正确的基因组位置？ 2)识别相似顺式元件的转录因子之间的竞争如何调节在发育过程中形成活跃的染色质结构域？ 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介导整个细胞的协调基因激活，包括rDNA基因座、组蛋白基因座和剂量补偿雄性的基因组 X染色体，所有这些都必须在发育中的胚胎中被适当激活。我研究计划最初集中在这些基本的染色质结构域中的两个，果蝇中的协调基因激活：1）剂量补偿X染色体，性别间的基因剂量和2）组蛋白基因座体（HLB），协调调节组蛋白基因表达。果蝇是理想的研究生物由于染色质结构域的快速和同步化，这是由于基因组技术的发展以及大量的遗传和生物化学工具以及可用的基因组数据集。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，关于在特定基因组位点驱动它们形成的分子机制知之甚少在早期发展中。确定活跃男性的染色质区域 X染色体和HLB的建立和维持随着发育时间的推移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，调节两个细胞的形成，剂量补偿的X染色体和HLB活性染色质结构域，为我们提供了一个进入点揭示新的见解动态过程的染色质结构域阵我们工作的意义在于我们将定义活跃的染色质结构域如何形成并将寻求确定共同的潜在机制，在特定的基因组位点形成两个非常不同的结构域。