Computational Model of Gene Regulatory Program

项目摘要/摘要 基因调控网络(GRN)是代表基因组调控密码的模型 直接控制胚胎发育的过程，也控制胚胎后的构建 身体计划，包括器官发生。目前这些模型中最先进的是海胆 内胚层GRN.这个GRN规定了调控基因之间的相互作用，这些基因是 监管守则，就监管逻辑而言，它位于监管的所有其他方面的上游 系统包括microRNAs、染色质修饰和转录生物化学。在本期 在我们正在寻求续签的赠款中，我们开发了BioTapestry作为计算平台 内胚层GRN的表达，包括调控DNA的直接功能意义 序列、基因编码控制系统的体系结构、GRN的时间和空间活动 相互作用，以及与基础实验数据的广泛联系。BioTapestry现在是领先的 用于GRN分析和演示的工具。由这笔赠款支持的项目的计算方面 与GRN性质的实验探索密不可分，GRN的性质也是如此 这份续签提案。新的计算目标包括对BioTapestry的巨大增强，以便它 将具有从实验数据计算GRN结构的独特能力，并向 需要进一步信息的调查人员方面。第二个计算目标是开发一种 一套利用GRN内基因活动的时间进程测量来计算 GRN执行特定发育功能的亚回路的动力学行为，以及测试 结果与观测数据相比较。我们还将开发计算设备来评估 GRN解释观察到的基因表达模式。然而，充足最终必须是 通过实验进行评估。提出了两项与计算评估相关联的主要举措 解释充分：首先，我们将开发全新的多路顺式调控方法 模块识别和实验分析，我们将使用这些来验证GRN的预测 或大多数GRN节点。作为对《GRN》解释力充分性的最终挑战，我们 将使用合成方法，通过在重新设计的BAC中构建调节子电路，这应该 足以产生预期的发展结果。它们将被插入海胆卵和海里 确定它们是否真的产生了预测的基因发育模式 它们通常不会出现的上下文中的表达式。项目叙事 这是一个基础研究项目，针对的是了解什么动物的根本挑战 基因组指的是，特别是动物根据进化而发育的生命过程的一个方面 遗传的、物种特定的基因组程序。基因组控制系统是复杂的逻辑处理 需要为理解和分析而定制设计的计算设备的机构。我们 将在已经是世界领先的处理这些问题的计算平台上创造新的潜力 控制系统，我们将通过实验测试我们对它们的理解的充分性，这个项目 将直接与所有动物基因组控制系统相关，包括我们自己的。

PROJECT SUMMARY / ABSTRACT Gene regulatory networks (GRN) are models which represent the genomic regulatory code that directly controls the processes of embryonic development, and also the postembryonic construction of the body plan, including organogenesis. The most advanced of these models at present is the sea urchin endomesoderm GRN. This GRN specifies the interactions of regulatory genes that are the direct output of the regulatory code, and that in terms of regulatory logic lie upstream of all other aspects of the regulatory system including microRNAs, chromatin modifications and transcription biochemistry. In the current period of the Grant for which we are seeking renewal, we developed BioTapestry as the computational platform for representation of the endomesoderm GRN, including direct functional significance of regulatory DNA sequence, architecture of the genomically encoded control system, temporal and spatial activity of GRN interactions, and extensive linkage to the underlying experimental data. BioTapestry is now the leading vehicle for GRN analysis and presentation. The computational aspect of the project supported by this grant has been inseparably intertwined with experimental exploration of GRN properties, and the same is true of this renewal proposal. New computational objectives include a vast enhancement of BioTapestry so that it will have the unique capacities of computing GRN architecture from experimental data, and indicating to the investigator aspects in need of further information. A second computational objective is development of a set of methods for utilizing time course measurements of activities of genes within the GRN to compute the kinetic behavior of the subcircuits of the GRN that execute particular developmental functions, and testing the results vs. observed data. We will also develop computational apparatus for assessing the sufficiency of the GRN in explaining the observed patterns of gene expression. However, sufficiency must ultimately be assessed experimentally. Two major initiatives are proposed to interlock with the computational assessment of sufficiency of explanation: first, we will develop entirely new multiplexed methods for cis-regulatory module identification and experimental analysis, and we will use these to verify predictions of the GRN at all or most GRN nodes. As an ultimate challenge to the sufficiency of the explanatory power of the GRN, we will use a synthetic approach, by constructing regulatory subcircuits in re-engineered BACs, that should suffice to produce a predicted developmental outcome. They will be inserted into sea urchin eggs and sea star eggs to determine whether they indeed generate the predicted developmental patterns of gene expression in contexts where they would not normally appear. PROJECT NARRATIVE This is a basic research project directed at the fundamental challenge of understanding what animal genomes mean, in particular that aspect of life process by which animals develop according to evolutionarily inherited, species specific genomic programs. Genomic control systems are complex logic processing mechanisms that require custom designed, computational apparatus for understanding and analysis. We will create new potentialities in what is already the world's leading computational platform for handling these control systems, and we will experimentally test the sufficiency of our understanding of them, a project that will be immediately relevant to all animal genomic control systems including our own.