Abstract
Pancreatic β-cells require the coordinated expression of transcription factors such as MAFA to dynamically secrete insulin to maintain euglycemia. We previously identified that a naturally occurring mutation in MAFA (MAFA (S64F) ) predisposes carriers to divergent conditions of either maturity (adult)-onset diabetes of the young (MODY) or hypoglycemia in a sex-dependent manner, and we modeled these phenotypes in mice expressing this MafA variant. Here we show that the genetic background in mice can modulate penetrance of the male glycemic phenotype: heterozygous MafA (S64F/+) males backcrossed on a C57/Bl6J ('C57') background prevents this pathology with improved insulin secretion, while MafA (S64F/+) males on a mixed background (C57 with SJL) manifest overt diabetes and impaired insulin secretion by 5 weeks of age due (in part) to accelerated β-cell senescence. In contrast, female mice on either background (mixed or backcrossed C57) similarly show hypoglycemia. Bulk RNAseq on male C57/Bl6J islets revealed fewer differentially expressed genes (DEGs) and a more similar profile to MafA (WT) males than MafA (S64F/+) males on the mixed background, including abrogation of β-cell senescence and intact expression of circadian regulators. CUT&RUN mapping revealed that MafA likely regulates several of the DEGs identified in both C57 and mixed genetic backgrounds. Our analysis also identified increased expression of many islet-enriched transcription factors directly regulating MafA expression (e.g., Pdx1) and increased MafA protein levels in C57 MafA (S64F/+) males. In sum, these data suggest that the penetrance of diabetes caused MAFA (S64F) activity in male human islet β-cells may be modulated by genetic background to impact β-cell senescence, circadian regulation, and islet function.