Abstract
Pancreatic α-cells are central regulators of glucose and amino acid homeostasis, yet the mechanisms that preserve α-cell identity and function remain incompletely understood. N6-methyladenosine (m6A) is a widespread mRNA modification that is essential for β-cell biology and pancreatic endocrine differentiation. Here we show that m6A is a key regulator of α-cell function and plasticity. In α-cells, metabolic cues that stimulate glucagon secretion such as L-arginine increase METTL3, METTL14 and m6A levels. Loss of m6A impairs amino acid-stimulated glucagon secretion, disrupts α-cell identity programmes and induces metabolic rewiring. In mice, α-cell-specific Mettl14 deletion reduces α-cell mass, increases β-cell mass and promotes α-to-β-cell conversion, accompanied by the emergence of late β-like states with features of incomplete maturation. Mechanistically, m6A-eCLIP identifies Yy1 as a direct m6A-sensitive target, and elevated YY1 links m6A loss to signalling rewiring and erosion of α-cell identity. These findings identify m6A as a central regulator of α-cell state and reveal an epitranscriptomic mechanism controlling endocrine cell plasticity.