Evolutionary models for gene regulatory networks

描述（由申请人提供） 摘要：该项目将使用多能干细胞和植入前胚胎发育的分析作为试验问题，以建立和测试基因调控网络（GRNs）的定量进化模型。多能性是指未分化细胞分化成三个胚层中的任何一个并产生任何成体细胞类型的潜力。该项目的一般假设是，多能细胞表型可以通过跨物种交替实施（重新连接）GRNs来维持。这一假设推断，GRNs重新布线的知识将有助于找到新的途径和有效的方法，将体细胞重编程为多能状态。这一假设将解决GRN重建和定量系统发育模型GRN进化的多模态数据相结合的方法。这些模型将适用于识别和分析其他物种和其他生物过程中的GRNs。该项目将建立一个通用的概率框架，以实现基因组，表观基因组和转录组数据的联合分析，以及GRNs符合和实施的组合和进化规则的推断。将制定以下五个研究重点。1.建立GRN分析的概率框架。2.开发模型与顺式调控模块（CRM）的TF的组合相互作用，并扩展此模型，将表观遗传状态的CRM。3.建立概率进化模型，用于鉴定保守的和物种特异性的基因表达模块. 4.开发一个进化模型，用于分析GRNs的重新布线。模型将模拟TF与靶基因、CRMs和靶基因表达水平的调控关系的协同进化。5.识别支持哺乳动物多能细胞身份的GRNs的保守和重新连接的组件。在人类和小鼠胚胎干细胞中实验测试这些保守的和物种特异性的调控关系。 公共卫生相关性：该项目将使用多能干细胞和植入前胚胎发育的分析作为试验问题，以建立和测试基因调控网络的定量进化模型。该项目将解决基因表达是如何在多能干细胞中调节的，以及这种基因调控网络是如何进化的。这些信息可能会导致发现新的和更有效的细胞重编程途径，这对开发各种疾病的细胞疗法至关重要。

DESCRIPTION (Provided by the applicant) Abstract: This project will use the analysis of pluripotent stem cells and pre-implantation embryonic development as testbed questions to build and test quantitative evolutionary models for gene regulatory networks (GRNs). Pluripotency refers to the potential of an undifferentiated cell to differentiate into any of the three germ layers and give rise to any adult cell type. The general hypothesis of the project is that the pluripotent cell phenotype can be sustained by alternatively implemented (re-wired) GRNs across species. This hypothesis deduces that the knowledge of the re-wiring of GRNs will contribute to finding new routes and efficient methods for reprogramming somatic cells into a pluripotent state. This hypothesis will be addressed by developing methods for combining multi-modality data for GRN reconstruction and quantitative phylogenetic models for GRN evolution. These models will be applicable for identifying and analyzing GRNs in other species and other biological processes. This project will build a general probabilistic framework to enable joint analysis of genomic, epigenomic and transcriptomic data as well as inference of combinatorial and evolutionary rules that GRNs conform to and implement. Five research thrusts will be developed as follows. 1. Develop a probabilistic framework for GRN analysis. 2. Develop models for combinatorial interactions of TFs with a cis-regulatory module (CRM), and extend this model to incorporate epigenetic states of the CRM. 3. Develop probabilistic evolution models for identification of conserved and species- specific gene expression modules. 4. Develop an evolutionary model for analysis of re-wiring of GRNs. The co-evolution of the regulatory relationships of TF and target genes, CRMs and the expression levels of target genes will be modeled. 5. Identify the conserved and re-wired components of the GRNs that support the pluripotent cell identity mammals. Experimentally test these conserved and species-specific regulatory relationships in human and mouse embryonic stem cells. Public Health Relevance: This project will use the analysis of pluripotent stem cells and pre-implantation embryonic development as testbed questions to build and test quantitative evolutionary models for gene regulatory networks. This project will address how gene expression is regulated in pluripotent stem cells and how such gene regulatory networks evolve. Such information may lead to finding new and more efficient routes of cellular reprogramming, which is critical to the development of cell-based therapies for various diseases.