Landscape of transcriptome-wide m6A modification in diabetic liver reveals rewiring of PI3K-Akt signaling after physical exercise

Aim

Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6-methyladenosine (m⁶A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome-wide m⁶A alterations in molecular adaptations after physical exercise have yet to be fully elucidated.

Methods

Four-week-old male C57BL/6J mice received a high-fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m⁶A methylome was examined, the conjoint MeRIP-seq and RNA-seq was performed, and the exercise-modulated genes were confirmed.

Results

Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m⁶A. By analyzing the distribution of m⁶A in transcriptomes, an abundance of m⁶A throughout mRNA transcripts and a pattern of conserved m⁶A after physical exercise was identified. It is noteworthy that conjoint MeRIP-seq and RNA-seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K-Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise-mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m⁶A-dependent manner.

Conclusion

These findings highlight the pivotal role of the exercise-induced m⁶A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling.