FunDMDeep-m⁶A: Identification and prioritization of functional differential m⁶A methylation genes

Motivation: As the most abundant mammalian mRNA methylation, N⁶-methyladenosine (m⁶A) exists in >25% of human mRNAs and is involved in regulating many different aspects of mRNA metabolism, stem cell differentiation and diseases like cancer. However, our current knowledge about dynamic changes of m⁶A levels and how the change of m⁶A levels for a specific gene can play a role in certain biological processes like stem cell differentiation and diseases like cancer is largely elusive. Results: To address this, we propose in this paper FunDMDeep-m⁶A a novel pipeline for identifying context-specific (e.g. disease versus normal, differentiated cells versus stem cells or gene knockdown cells versus wild-type cells) m⁶A-mediated functional genes. FunDMDeep-m⁶A includes, at the first step, DMDeep-m⁶A a novel method based on a deep learning model and a statistical test for identifying differential m⁶A methylation (DmM) sites from MeRIP-Seq data at a single-base resolution. FunDMDeep-m⁶A then identifies and prioritizes functional DmM genes (FDmMGenes) by combing the DmM genes (DmMGenes) with differential expression analysis using a network-based method. This proposed network method includes a novel m⁶A-signaling bridge (MSB) score to quantify the functional significance of DmMGenes by assessing functional interaction of DmMGenes with their signaling pathways using a heat diffusion process in protein-protein interaction (PPI) networks. The test results on 4 context-specific MeRIP-Seq datasets showed that FunDMDeep-m⁶A can identify more context-specific and functionally significant FDmMGenes than m⁶A-Driver. The functional enrichment analysis of these genes revealed that m⁶A targets key genes of many important context-related biological processes including embryonic development, stem cell differentiation, transcription, translation, cell death, cell proliferation and cancer-related pathways. These results demonstrate the power of FunDMDeep-m⁶A for elucidating m⁶A regulatory functions and its roles in biological processes and diseases.