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

Abstract

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.

Natural antisense transcripts as drug targets

“…m6A is deposited co-transcriptionally, likely by the METTL3/METTL14/WTAP m6A methyltransferase complex (MTC) within nuclear speckles. m6A can be dynamically removed by "erasers" such as FTO (FTO alpha-ketoglutaratedependent dioxygenase) or ALKBH5 (AlkB homolog 5, RNA demethylase) in response to environmental stimuli including memory formation, cancer development and stress responses (Wang et al, 2020;Vaasjo 2022).…”

“…miRNAs were also shown to mediate binding of Mettl3 to target sites on mRNAs. m6A modification of 5′UTRs is thought to be involved in cap-independent translation and thus facilitates the cellular stress response (Vaasjo 2022).…”

“…Although yet therapeutically untapped, modulation of m6A modification using NBTs could allow context-dependent control of disease-relevant protein expression. Due to intense investigations into the role and changes in m6A patterning in brain development, neuronal activity and epithelialmesenchymal transition, this goal may be achieved in the near future (Chen Y. et al, 2020;Vaasjo 2022).…”