Systematic identification of transcriptional and post-transcriptional regulations in human respiratory epithelial cells during influenza A virus infection

Background: Respiratory epithelial cells are the primary target of influenza virus infection in human. However, the molecular mechanisms of airway epithelial cell responses to viral infection are not fully understood. Revealing genome-wide transcriptional and post-transcriptional regulatory relationships can further advance our understanding of this problem, which motivates the development of novel and more efficient computational methods to simultaneously infer the transcriptional and post-transcriptional regulatory networks. Results: Here we propose a novel framework named SITPR to investigate the interactions among transcription factors (TFs), microRNAs (miRNAs) and target genes. Briefly, a background regulatory network on a genome-wide scale (similar to 23,000 nodes and similar to 370,000 potential interactions) is constructed from curated knowledge and algorithm predictions, to which the identification of transcriptional and post-transcriptional regulatory relationships is anchored. To reduce the dimension of the associated computing problem down to an affordable size, several topological and data-based approaches are used. Furthermore, we propose the constrained LASSO formulation and combine it with the dynamic Bayesian network (DBN) model to identify the activated regulatory relationships from time-course expression data. Our simulation studies on networks of different sizes suggest that the proposed framework can effectively determine the genuine regulations among TFs, miRNAs and target genes; also, we compare SITPR with several selected state-of-the-art algorithms to further evaluate its performance. By applying the SITPR framework to mRNA and miRNA expression data generated from human lung epithelial A549 cells in response to A/Mexico/InDRE4487/2009 (H1N1) virus infection, we are able to detect the activated transcriptional and post-transcriptional regulatory relationships as well as the significant regulatory motifs. Conclusion: Compared with other representative state-of-the-art algorithms, the proposed SITPR framework can more effectively identify the activated transcriptional and post-transcriptional regulations simultaneously from a given background network. The idea of SITPR is generally applicable to the analysis of gene regulatory networks in human cells. The results obtained for human respiratory epithelial cells suggest the importance of the transcriptional, post-transcriptional regulations as well as their synergies in the innate immune responses against IAV infection.