DRUM: Inference of Disease-Associated m6A RNA Methylation Sites From a Multi-Layer Heterogeneous Network

Recent studies have revealed that the RNA N-6-methyladenosine (m(6)A) modification plays a critical role in a variety of biological processes and associated with multiple diseases including cancers. Till this day, transcriptome-wide m(6)A RNA methylation sites have been identified by high-throughput sequencing technique combined with computational methods, and the information is publicly available in a few bioinformatics databases; however, the association between individual m(6)A sites and various diseases are still largely unknown. There are yet computational approaches developed for investigating potential association between individual m(6)A sites and diseases, which represents a major challenge in the epitranscriptome analysis. Thus, to infer the disease-related m(6)A sites, we implemented a novel multi-layer heterogeneous network-based approach, which incorporates the associations among diseases, genes and m(6)A RNA methylation sites from gene expression, RNA methylation and disease similarities data with the Random Walk with Restart (RWR) algorithm. To evaluate the performance of the proposed approach, a ten-fold cross validation is performed, in which our approach achieved a reasonable good performance (overall AUC: 0.827, average AUC 0.867), higher than a hypergeometric test-based approach (overall AUC: 0.7333 and average AUC: 0.723) and a random predictor (overall AUC: 0.550 and average AUC: 0.486). Additionally, we show that a number of predicted cancer-associated m(6)A sites are supported by existing literatures, suggesting that the proposed approach can effectively uncover the underlying epitranscriptome circuits of disease mechanisms. An online database DRUM, which stands for disease-associated ribonucleic acid methylation, was built to support the query of disease-associated RNA m(6)A methylation sites, and is freely available at: www.xjtlu.edu.cn/biologicalsciences/drum.