Landscape of transcriptome-wide mA 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 (mA) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome-wide mA 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 mA 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 mA. By analyzing the distribution of mA in transcriptomes, an abundance of mA throughout mRNA transcripts and a pattern of conserved mA 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 mA-dependent manner.

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