University of São Paulo, Bioinformatics Graduate Program, São Carlos, SP, Brazil.
Institute of Science and Technology, Federal University of São Paulo, São José dos Campos, SP, Brazil.
Sci Rep. 2020 Aug 6;10(1):13303. doi: 10.1038/s41598-020-70145-4.
All cellular processes can be ultimately understood in terms of respective fundamental biochemical interactions between molecules, which can be modeled as networks. Very often, these molecules are shared by more than one process, therefore interconnecting them. Despite this effect, cellular processes are usually described by separate networks with heterogeneous levels of detail, such as metabolic, protein-protein interaction, and transcription regulation networks. Aiming at obtaining a unified representation of cellular processes, we describe in this work an integrative framework that draws concepts from rule-based modeling. In order to probe the capabilities of the framework, we used an organism-specific database and genomic information to model the whole-cell biochemical network of the Mycoplasma genitalium organism. This modeling accounted for 15 cellular processes and resulted in a single component network, indicating that all processes are somehow interconnected. The topological analysis of the network showed structural consistency with biological networks in the literature. In order to validate the network, we estimated gene essentiality by simulating gene deletions and compared the results with experimental data available in the literature. We could classify 212 genes as essential, being 95% of them consistent with experimental results. Although we adopted a relatively simple organism as a case study, we suggest that the presented framework has the potential for paving the way to more integrated studies of whole organisms leading to a systemic analysis of cells on a broader scale. The modeling of other organisms using this framework could provide useful large-scale models for different fields of research such as bioengineering, network biology, and synthetic biology, and also provide novel tools for medical and industrial applications.
所有的细胞过程都可以最终归结为分子之间相应的基本生化相互作用，并可以将这些相互作用建模为网络。通常情况下，这些分子被不止一个过程所共享，因此它们相互连接。尽管存在这种影响，但细胞过程通常是通过具有不同详细程度的分离网络来描述的，例如代谢、蛋白质-蛋白质相互作用和转录调控网络。为了获得细胞过程的统一表示，我们在这项工作中描述了一个集成框架，该框架借鉴了基于规则的建模的概念。为了探究该框架的能力，我们使用了特定于生物体的数据库和基因组信息来对支原体（Mycoplasma genitalium）的全细胞生化网络进行建模。该建模涵盖了 15 个细胞过程，并生成了一个单一组件的网络，表明所有过程都在某种程度上相互关联。网络的拓扑分析显示出与文献中的生物网络具有结构一致性。为了验证该网络，我们通过模拟基因缺失来估计基因的必需性，并将结果与文献中可用的实验数据进行比较。我们可以将 212 个基因分类为必需基因，其中 95%与实验结果一致。尽管我们采用了相对简单的生物体作为案例研究，但我们认为所提出的框架具有为更全面的整体生物体研究铺平道路的潜力，从而在更广泛的范围内对细胞进行系统分析。使用该框架对其他生物体进行建模可以为生物工程、网络生物学和合成生物学等不同研究领域提供有用的大规模模型，并为医疗和工业应用提供新的工具。
