title: Systematic identification of transcriptional and post-transcriptional regulations in human respiratory epithelial cells during influenza A virus infection.
abstract: 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 (~23,000 nodes and ~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.
  
  
  CONCLUSIONS
  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.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Liu
authors.forename: Hulin
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY 14642, USA. jian_zhu@urmc.rochester.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Miao
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D014157:Transcription Factors