The miR-203/ZBTB20/MAFA axis orchestrates pancreatic β-cell maturation and identity during weaning and diabetes

ABSTRACT Maturation of postnatal β cells is regulated in a cell-autonomous manner, and metabolically stressed β cells regress to an immature state, ensuring defective β-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to β-cell maturation remain largely unknown. Here, we report a miR-203/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that miR-203 level in β cells changes during the nutritional transition and that miR-203 inhibits β-cell maturation at the neonatal stage and under high-fat diet (HFD) conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature β cells into CgBHi endocrine cells, while suppressing gene expressions associated with β-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional β-cell numbers to alleviate diabetes. Highlights Nutritional transition from high-fat-rich diet to carbohydrate-rich diet inhibits miR-203 expression. Failure to inhibition of miR-203 during HFD feeding causes β-cell immaturity and loss of identity. Ablation of miR-203 in β cells prevents HFD-induced β-cell dysfunction. The miR-203-ZBTB20-MAFA axis mediates β-cell immaturity and is conserved in humans.