title: Inferring RBP-Mediated Regulation in Lung Squamous Cell Carcinoma.
abstract: RNA-binding proteins (RBPs) play key roles in post-transcriptional regulation of mRNAs. Dysregulations in RBP-mediated mechanisms have been found to be associated with many steps of cancer initiation and progression. Despite this, previous studies of gene expression in cancer have ignored the effect of RBPs. To this end, we developed a lasso regression model that predicts gene expression in cancer by incorporating RBP-mediated regulation as well as the effects of other well-studied factors such as copy-number variation, DNA methylation, TFs and miRNAs. As a case study, we applied our model to Lung squamous cell carcinoma (LUSC) data as we found that there are several RBPs differentially expressed in LUSC. Including RBP-mediated regulatory effects in addition to the other features significantly increased the Spearman rank correlation between predicted and measured expression of held-out genes. Using a feature selection procedure that accounts for the adaptive search employed by lasso regularization, we identified the candidate regulators in LUSC. Remarkably, several of these candidate regulators are RBPs. Furthermore, majority of the candidate regulators have been previously found to be associated with lung cancer. To investigate the mechanisms that are controlled by these regulators, we predicted their target gene sets based on our model. We validated the target gene sets by comparing against experimentally verified targets. Our results suggest that the future studies of gene expression in cancer must consider the effect of RBP-mediated regulation.
authors.affiliation: Department of Health Informatics, Middle East Technical University, Ankara, Turkey.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Lafzi
authors.affiliation: Department of Computer Engineering, Antalya International University, Antalya, Turkey.
authors.forename: Hilal
authors.initials: H
authors.lastname: Kazan
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors