Integrative network analysis identifies cell-specific trans regulators of m6A

N6-methyladenosine (m(6)A) is a reversible and dynamic RNA modification in eukaryotes. However, how cells establish cell-specific m(6)A methylomes is still poorly understood. Here, we developed a computational framework to systematically identify cell-specific trans regulators of m(6)A through integrating gene expressions, binding targets and binding motifs of large number of RNA binding proteins (RBPs) with a co-methylation network constructed using large-scale m(6)A methylomes across diverse cell states. We applied the framework and successfully identified 32 high-confidence m(6)A regulators that modulated the variable m(6)A sites away from stop codons in a cell-specific manner. To validate them, we knocked down three regulators respectively and found two of them (TRA2A and CAPRIN1) selectively promoted the methylations of the m(6)A sites co-localized with their binding targets on RNAs through physical interactions with the m(6)A writers. Knockdown of TRA2A increased the stabilities of the RNAs with TRA2A bound near the m(6)A sites and decreased the viability of cells. The successful identification of m(6)A regulators demonstrates a powerful and widely applicable strategy to elucidate the cell-specific m(6)A regulators. Additionally, our discovery of pervasive trans-acting regulating of m(6)A provides novel insights into the mechanisms by which spatial and temporal dynamics of m(6)A methylomes are established.