m6A mRNA methylation regulates pancreatic α-cell plasticity

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. m6A methylation acts as an epitranscriptomic regulator of endocrine cell identity in pancreatic islet alpha cells, with loss of m6A leading to impaired alpha cell identity, α- to β-cell conversion and metabolic rewiring of islet endocrine cells.