RFX6 maintains gene expression and function of adult human islet α cells

Mutations in the gene encoding the transcription factor RFX6 are associated with human diabetes mellitus. Within pancreatic islets, RFX6 expression is most abundant in islet α cells, and α cell RFX6 expression is altered in diabetes. However, the roles of RFX6 in regulating gene expression, glucagon output and other crucial human adult α cell functions are not yet understood. We developed a method for selective genetic targeting of human α cells and assessed RFX6-dependent α cell function. RFX6 suppression with RNA interference led to impaired α cell exocytosis and dysregulated glucagon secretion in vitro and in vivo. By contrast, these phenotypes were not observed with RFX6 suppression across all islet cells. Transcriptomics in α cells revealed RFX6-dependent expression of genes governing nutrient sensing, hormone processing, and secretion, with some of these exclusively expressed in human α cells. Mapping of RFX6 DNA-binding sites in primary human islet cells identified a subset of direct RFX6 target genes. Together, these data unveil RFX6-dependent genetic targets and mechanisms crucial for regulating adult human α cell function.