Improved reconstruction of in silico gene regulatory networks by integrating knockout and perturbation data.

We performed computational reconstruction of the in silico gene regulatory networks in the DREAM3 Challenges. Our task was to learn the networks from two types of data, namely gene expression profiles in deletion strains (the 'deletion data') and time series trajectories of gene expression after some initial perturbation (the 'perturbation data'). In the course of developing the prediction method, we observed that the two types of data contained different and complementary information about the underlying network. In particular, deletion data allow for the detection of direct regulatory activities with strong responses upon the deletion of the regulator while perturbation data provide richer information for the identification of weaker and more complex types of regulation. We applied different techniques to learn the regulation from the two types of data. For deletion data, we learned a noise model to distinguish real signals from random fluctuations using an iterative method. For perturbation data, we used differential equations to model the change of expression levels of a gene along the trajectories due to the regulation of other genes. We tried different models, and combined their predictions. The final predictions were obtained by merging the results from the two types of data. A comparison with the actual regulatory networks suggests that our approach is effective for networks with a range of different sizes. The success of the approach demonstrates the importance of integrating heterogeneous data in network reconstruction.