The miR-203/ZBTB20/MAFA Axis Orchestrates Pancreatic β-Cell Maturation and Identity During Weaning and Diabetes

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 mature form of miRNA (miR-203)/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that the level of the mature form of miRNA (miR-203) 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 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.