Computational and Functional Analysis of Gene Networks

描述：(由申请人提供)后生动物的发展需要 细胞间信号和这些信号在细胞内的整合 产生转录反应。虽然许多信号通路都很好 在全球范围内对信号之间的相互作用进行表征和理解 转导和基因转录--基因调控网络--仍然是 当前基因组学研究面临的主要挑战。我们已经详细地探索了一部分 一个这样的网络，它指定了果蝇肌肉的一个子集的命运 和心脏祖细胞通过三种信号的共同作用 途径，包括通过表皮生长因子和成纤维细胞生长因子受体输入的RAS途径。 这些途径下游的转录因子，以及组织特异性的 由它们诱导的因子整合在单一的转录增强子中 对于祖先身份基因，偶数跳过肌肉和心脏增强器 (MHE)对果蝇基因组的最新测序提供了一个令人兴奋的 有机会扩展从我们对MHE的调查中获得的见解 在全基因组范围内。在这里，将使用计算分析来确定 顺式调控元件，具有MHE的共同特征，并对 中胚层基因以类似的时空模式表达。活体内 技术，包括分析报告基因，将被用来 验证计算机的预测。监管机构的信令组件 这些顺式调节元件在其中发挥作用的网络将使用 DNA微阵列。成纤维细胞生长因子和表皮生长因子受体各自的作用 RAS介导的中胚层信号通路，非RAS介导的活性 这些受体，以及特定RAS的个体贡献 转录效应将被确定，转录效应的综合效应将被确定 多种生长因子信号。这些方法将显著增加 我们对组合信号和转录反应的理解 识别新的基因和调控元件，并提供对 基因调控网络，调节对特定信号的反应 监管背景。 这项建议中详细的研究将为候选人提供一个理想的 有机会将发展遗传学的强大背景应用于 计算和功能基因组学的新兴领域丰富的学习和 研究环境，为独立的学术研究做准备 职业生涯。

DESCRIPTION: (provided by applicant) Metazoan development requires both intercellular signaling and the integration of these signals within cells to produce a transcriptional response. While many signaling pathways are well characterized, understanding on a global scale the interplay between signal transduction and gene transcription - genetic regulatory networks -remains a major challenge for current genomics research. We have explored in detail part of one such network, which specifies the fate of a subset of Drosophilamuscle and cardiac progenitor cells by the combined action of three signaling pathways, including the Ras pathway via input from both EGF and FGF receptors. The transcription factors downstream of these pathways, and tissue-specific factors induced by them, are integrated at a single transcriptional enhancer for a progenitor identity gene, the even skippedMuscle and Heart Enhancer (MHE). Therecent sequencing of the Drosophilagenome offers an exciting opportunity to extend the insights garnered from our investigation of the MHE on a genome-wide scale. Here, a computational analysis will be used to identify cis-regulatory elements that share features of the MHE and that regulate mesodermal gene expression in a similar spatiotemporal pattern. Invivo techniques, including the analysis of reporter transgenes, will be used to validate the computer predictions. The signaling component of the regulatory networks in which these cisregulatory elements act will be investigated using DNA microarrays. The respective contributions of the FGF and EGF-receptor pathways to Ras-mediated mesodermal signaling, non-Ras-mediated activities of these receptors, and the individual contributions of specific Ras transcriptional effectors will be determined, as will the combined effects of multiple growth factor signals. These approaches will significantly increase our understanding of combinatorial signaling and transcriptional responses by identifying new genes and regulatory elements, and provide insight into the genetic regulatory networks that mediate responses to signaling in a specific regulatory context. The research detailed in this proposal will provide the candidate with an ideal opportunity to apply a strong background in developmental genetics to the emerging fields of computational and functional genomics in a rich learning and research environment, in preparation for an independent academic research career.