LncRNAs and Chromatin Modifications Pattern m⁶A Methylation at the Untranslated Regions of mRNAs

New roles for RNA in mediating gene expression are being discovered at an alarming rate. A broad array of pathways control patterning of N⁶-methyladenosine (m⁶A) methylation on RNA transcripts. This review comprehensively discusses long non-coding RNAs (lncRNAs) as an additional dynamic regulator of m⁶A methylation, with a focus on the untranslated regions (UTRs) of mRNAs. Although there is extensive literature describing m⁶A modification of lncRNA, the function of lncRNA in guiding m⁶A writers has not been thoroughly explored. The independent control of lncRNA expression, its heterogeneous roles in RNA metabolism, and its interactions with epigenetic machinery, alludes to their potential in dynamic patterning of m⁶A methylation. While epigenetic regulation by histone modification of H3K36me3 has been demonstrated to pattern RNA m⁶A methylation, these modifications were specific to the coding and 3'UTR regions. However, there are observations that 5'UTR m⁶A is distinct from that of the coding and 3'UTR regions, and substantial evidence supports the active regulation of 5'UTR m⁶A methylation. Consequently, two potential mechanisms in patterning the UTRs m⁶A methylation are discussed; (1) Anti-sense lncRNA (AS-lncRNA) can either bind directly to the UTR, or (2) act indirectly via recruitment of chromatin-modifying complexes to pattern m⁶A. Both pathways can guide the m⁶A writer complex, facilitate m⁶A methylation and modulate protein translation. Findings in the lncRNA-histone-m⁶A axis could potentially contribute to the discovery of new functions of lncRNAs and clarify lncRNA-m⁶A findings in translational medicine.