Using epigenomics data to predict gene expression in lung cancer

Jeffery Li, Travers Ching, Sijia Huang, Lana X Garmire

Epigenetic alterations are known to correlate with changes in gene expression among various diseases including cancers. However, quantitative models that accurately predict the up or down regulation of gene expression are currently lacking. A new machine learning-based method of gene expression prediction is developed in the context of lung cancer. This method uses the Illumina Infinium HumanMethylation450K Beadchip CpG methylation array data from paired lung cancer and adjacent normal tissues in The Cancer Genome Atlas (TCGA) and histone modification marker CHIP-Seq data from the ENCODE project, to predict the differential expression of RNA-Seq data in TCGA lung cancers. It considers a comprehensive list of 1424 features spanning the four categories of CpG methylation, histone H3 methylation modification, nucleotide composition, and conservation. Various feature selection and classification methods are compared to select the best model over 10-fold cross-validation in the training data set. A best model comprising 67 features is chosen by ReliefF based feature selection and random forest classification method, with AUC = 0.864 from the 10-fold cross-validation of the training set and AUC = 0.836 from the testing set. The selected features cover all four data types, with histone H3 methylation modification (32 features) and CpG methylation (15 features) being most abundant. Among the dropping-off tests of individual data-type based features, removal of CpG methylation feature leads to the most reduction in model performance. In the best model, 19 selected features are from the promoter regions (TSS200 and TSS1500), highest among all locations relative to transcripts. Sequential dropping-off of CpG methylation features relative to different regions on the protein coding transcripts shows that promoter regions contribute most significantly to the accurate prediction of gene expression. By considering a comprehensive list of epigenomic and genomic features, we have constructed an accurate model to predict transcriptomic differential expression, exemplified in lung cancer.