m6A-eCLIP sequencing in mouse alpha cell line aTC1-6 cells with Scramble or Mettl14 KD

I Previous studies have shown that m6A is involved in fine-tuning β-cell function, but its impact on α-cells, which secrete glucagon in response to low glucose and amino acids, has not been fully investigated. Here, we show that METTL14, a key m6A writer, is essential for maintaining α-cell function and identity.

Using a combination of in vitro and in vivo models, we demonstrate that metabolic stimuli such as low glucose and amino acids upregulate METTL14, enhancing glucagon secretion, while insulin downregulates it. Importantly, α-cell-specific knockout of Mettl14 in mice results in impaired glucagon secretion, increased insulin levels, and a surprising conversion of α-cells into β-cells. These findings reveal that m6A is a critical regulator of α-cell identity and function, expanding our understanding of RNA modifications in islet biology.