Emerging Orchestrator of Ecological Adaptation: m6A Regulation of Post-Transcriptional Mechanisms

Abstract

Genetic mechanisms have been at the forefront of our exploration into the substrate of adaptive evolution and phenotypic diversification. However, genetic variation only accounts for a fraction of phenotypic variation. In the last decade, the significance of RNA modification mechanisms has become more apparent in the context of organismal adaptation to rapidly changing environments. RNA m⁶A methylation, the most abundant form of RNA modification, is emerging as a potentially significant player in various biological processes. Despite its fundamental function to regulate other major post-transcriptional mechanisms such as microRNA and alternative splicing, its role in ecology and evolution has been understudied. This review highlights the potential importance of m⁶A RNA methylation in ecological adaptation, emphasising the need for further research, especially in natural systems. We focus on how m⁶A not only affects mRNA fate but also influences miRNA-mediated gene regulation and alternative splicing, potentially contributing to organismal adaptation. The aim of this review is to synthesise key background information to enhance our understanding of m⁶A mechanisms driving species survival in dynamic environments and motivate future research into the dynamics of adaptive RNA methylation.

Keywords: adaptation; ecological genetics; molecular evolution; transcriptomics.

FIGURE 1

m⁶A RNA methylation in the context of environmental acclimation/adaptation. (A) This panel presents the current understanding of (post‐) transcriptional regulations in ecological adaptation. Darker shades indicate areas with less knowledge about the role of each mechanism. The first column highlights the primary knowledge gaps of each mechanism, marked by the corresponding shade, while the second column outlines potential outcomes if further studies are pursued in these areas. (B) This panel depicts a three‐way model of known regulatory interactions between m⁶A RNA modification, miRNA and alternative splicing. These reciprocal and interconnected regulatory interactions represent a variety of regulatory outcomes at the post‐transcriptional level, which could lead to a broad spectrum of molecular responses when each mechanism is differently influenced by external and internal stimuli. The arrows and blockheads indicate various stimulatory and inhibitory post‐transcriptional crosstalk between these processes. (C) This panel illustrates an example of how m⁶A RNA methylation contributes directly or indirectly to advantageous phenotypic variation in response to rapid environmental change—either through directly affecting mRNA fate or indirectly through the regulation of two major post‐transcriptional regulatory mechanisms (miRNA and alternative splicing) when exposed to environmental stimuli.

FIGURE 2

An example representing a three‐way investigation of m⁶A‐mediated regulation of transcriptional responses. (A) Standard laboratory methods and analyses to identify differences in mRNA, miRNA and m⁶A‐methylated RNAs (i.e., m⁶A–mRNA and m⁶A–miRNA) using the same biological samples. Conventional RNAseq methods can be used for all these quantifications; however, an immunopercipitation step is incorporated for the molecular enrichment of the m⁶A‐methylated RNAs prior to their sequencing (MeRIP‐seq method). (B) Integration of expression data from all the methods through combination of various correlation analyses (i.e., correlation between expression of miRNAs and mRNAs as well as their correlation with m⁶A levels on the same mRNA/miRNA transcripts). (C) Investigation of differences in correlations between all molecular components under distinct environmental conditions (e.g., to check if the correlations are present or absent under different conditions). (D) Prediction of regulatory axis between m⁶A methylation markers, miRNAs and target genes (e.g., through various binding site enrichment analyses of genes identified within each of the co‐expression module from the previous step). (E) Extension of the predicted axis through identification of differentially expressed isoforms of the identified regulators or their potential upstream effectors. The abbreviations R, W, E, TF and Mir‐(A, B, C) stand for reader, writer, eraser, transcription factor and microRNA‐(A, B, C), respectively.

FIGURE 3

Potential enhancement of adaptability to changing environments through m⁶A RNA modification. In the higher compartment, black arrows indicate regulatory interactions between major (post‐) transcriptional processes. In the lower compartment, minus and plus signs, respectively, indicate inhibition/decrease and enhancement/increase in the specified RNA‐related biological processes, and their colour codes imply on the underlying (post‐) transcriptional mechanism.