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Inferring transcriptional gene regulatory networks from transcriptomic datasets is a key challenge of systems biology, with potential impacts ranging from medicine to agronomy. There are several techniques used presently to experimentally assay transcription factors to target relationships, defining important information about real gene regulatory networks connections. These techniques include classical ChIP-seq, yeast one-hybrid, or more recently, DAP-seq or target technologies. These techniques are usually used to validate algorithm predictions. Here, we developed a reverse engineering approach based on mathematical and computer simulation to evaluate the impact that this prior knowledge on gene regulatory networks may have on training machine learning algorithms. First, we developed a gene regulatory networks-simulating engine called FRANK (Fast Randomizing Algorithm for Network Knowledge) that is able to simulate large gene regulatory networks (containing 104 genes) with characteristics of gene regulatory networks observed in vivo. FRANK also generates stable or oscillatory gene expression directly produced by the simulated gene regulatory networks. The development of FRANK leads to important general conclusions concerning the design of large and stable gene regulatory networks harboring scale free properties (built ex nihilo). In combination with supervised (accepting prior knowledge) support vector machine algorithm we (i) address biologically oriented questions concerning our capacity to accurately reconstruct gene regulatory networks and in particular we demonstrate that prior-knowledge structure is crucial for accurate learning, and (ii) draw conclusions to inform experimental design to performed learning able to solve gene regulatory networks in the future. By demonstrating that our predictions concerning the influence of the prior-knowledge structure on support vector machine learning capacity holds true on real data (Escherichia coli K14 network reconstruction using network and transcriptomic data), we show that the formalism used to build FRANK can to some extent be a reasonable model for gene regulatory networks in real cells., Gene Regulatory Networks: design and learning principles This work by Carré et al addresses central questions in biology, which are: how very large gene regulatory networks (GRNs) are organized, generate stable gene expression, and can be learnt using machine learning algorithms? In this work authors developed an algorithm able to simulate large GRNs. From these networks they simulate stable or oscillating gene expression and highlights some mathematical rules controlling such a collective (several thousands of genes) behavior. They discuss consequent hypothesis concerning the organization of GRNs in real cells. Using this simulation tool, authors also demonstrate that it’s likely possible to computationally learn GRNs from transcriptomic data and prior knowledge on the network (actual known connections issued from Yeast One Hybrid or ChIP Seq for instance). They particularly highlight the crucial importance of the prior knowledge structure in their capacity to learn large GRNs.