m(6)A-express: uncovering complex and condition-specific m(6)A regulation of gene expression

N(6)-methyladenosine (m(6)A) is the most abundant form of mRNA modification and controls many aspects of RNA metabolism including gene expression. However, the mechanisms by which m(6)A regulates cell- and condition-specific gene expression are still poorly understood, partly due to a lack of tools capable of identifying m(6)A sites that regulate gene expression under different conditions. Here we develop m(6)A-express, the first algorithm for predicting condition-specific m(6)A regulation of gene expression (m(6)A-reg-exp) from limited methylated RNA immunoprecipitation sequencing (MeRIP-seq) data. Comprehensive evaluations of m(6)A-express using simulated and real data demonstrated its high prediction specificity and sensitivity. When only a few MeRIP-seq samples may be available for the cellular or treatment conditions, m(6)A-express is particularly more robust than the log-linear model. Using m(6)A-express, we reported that m(6)A writers, METTL3 and METTL14, competitively regulate the transcriptional processes by mediating m(6)A-reg-exp of different genes in Hela cells. In contrast, METTL3 induces different m(6)A-reg-exp of a distinct group of genes in HepG2 cells to regulate protein functions and stress-related processes. We further uncovered unique m(6)A-reg-exp patterns in human brain and intestine tissues, which are enriched in organ-specific processes. This study demonstrates the effectiveness of m(6)A-express in predicting condition-specific m(6)A-reg-exp and highlights the complex, condition-specific nature of m(6)A-regulation of gene expression.