Gene regulatory network controlling commitment to ear identity

描述（申请人提供）：脊椎动物的内层是最复杂的感觉器官，负责听觉和平衡。然而在发育过程中，它是由一个简单的上皮细胞形成的。在耳发育过程中，多能祖细胞的潜能逐渐受到限制。这一过程由调控基因控制，其时空表达模式在一个精心安排的基因调控网络（GRN）中受到严格调控。我们和其他人已经建立了控制内耳祖细胞规范和决定的事件层次结构，并确定了一些相关的调控基因。基于这些信息，我们建立了一个控制这些过程的初步网络，并设计了一个分子筛选来识别新的生物特异性物质。我们已经定义了共同调节的基因组，它们反映了耳朵发育的不同阶段。我们现在将利用基因组序列信息、同时监测100多个基因表达变化的新技术以及新开发的生物信息学工具来建立和验证初步的GRN。具体来说，我们将：“鉴定对耳部诱导信号有反应的新基因”，建立耳部特异性转录因子和信号成分之间的上位性关系，“分离并表征控制耳部转录因子表达的增强子，并检查直接输入”，使用新开发的算法预测每个共表达组中基因的常见上游调节因子，并在体内测试预测的调节因子。这将揭示控制内耳祖细胞规范的基本GRN及其终端靶基因。未来，该GRN将作为研究蛋白质-蛋白质和蛋白质- dna相互作用的基础，建立完整的网络，对这一过程进行定量分析和数学建模，并为发现影响听力和平衡的人类疾病的新候选基因提供平台。

DESCRIPTION (provided by applicant): The vertebrate inner is the most complex of the sense organs responsible for hearing and balance. Yet during development it forms from a simple epithelium, the otic placode. During development of the ear, multipotent progenitor cells become progressively restricted in their potential. This process is controlled by regulatory genes whose temporal and spatial expression patterns are tightly regulated in an orchestrated gene regulatory network (GRN). We and others have established a hierarchy of events controlling the specification and determination of inner ear progenitors and identified some of the regulatory genes involved. Based on this information, we have established a preliminary network controlling these processes and designed a molecular screen to identify novel otic specifiers. We have defined co-regulated groups of genes that reflect different stages of ear specification. We will now harness genome sequence information, new technology to monitor changes in the expression of more than 100 genes simultaneously and newly developed bioinformatics tools to build up and verify the preliminary GRN. Specifically we will: " identify new genes responsive to otic inducing signals " establish the epistatic relationships between ear specific transcription factors and signaling components " isolated and characterize enhancers controlling transcription factor expression in the ear and examine direct inputs " predict common upstream regulators for genes in each synexpression group using newly developed algorithms and test the predicted regulators in vivo. This will uncover the basic GRN controlling the specification of inner ear progenitors together with its terminal target genes. In the future, this GRN will serve as a basis for studying protein-protein and protein-DNA interactions to build up a complete network, for quantitative analysis and mathematical modeling of this process, as well as a platform to discover new candidate genes for human disease affecting hearing and balance.