Genetic background modulates MafAS64F-mediated islet ageing in male mice

Abstract

Abstract Aims/hypothesis In monogenic diabetes, there is increasing recognition that common polygenic factors can modulate diabetes penetrance beyond the causative mutation(s). A naturally occurring mutation in the gene encoding the essential islet-enriched transcription factor MafA ( MafA S64F ) produces an unusually long-lived variant protein that predisposes male carriers to MODY. Here we investigated how genetic background modulates disease penetrance in Mafa S64F/+ male mice. Methods Mafa S64F/+ male mice, either on a mixed genetic background (C57BL/6J and SJL/J) or backcrossed to a C57BL/6J background, were assessed for glucose levels, beta cell function and gene signatures associated with cellular ageing. RNA-seq analysis was performed to identify unique differentially expressed genes (DEGS) and pathways in mixed-background or C57BL/6J Mafa S64F/+ male mouse islets. These were overlaid on MafA CUT&RUN peaks to identify direct targets that could differentially impact beta cell function in each background. Results Mafa S64F/+ male mice on a mixed background manifested overt diabetes, impaired insulin secretion, accelerated beta cell senescence and dysregulated circadian gene expression, while backcross to C57BL/6J prevented dysglycaemia and maintained insulin secretion in Mafa S64F/+ male mice, comparable with control littermates. RNA-seq of C57BL/6J Mafa S64F/+ male mouse islets revealed relative normalisation of DEGs associated with cellular ageing and circadian regulation. In addition, islets from C57BL/6J Mafa S64F/+ male mice showed unique downregulation of retinoic acid signalling and cell cycle inhibitor p21, the latter of which modulates cellular ageing and diabetes seen in the mixed-background mouse islets. CUT&RUN mapping revealed that MafA directly impacted expression of (at least) retinoic acid receptor-α (encoded by Rara ) in islets from C57BL/6J Mafa S64F/+ male mice and circadian regulation in islets from mixed-background mice. Conclusions/interpretation In sum, these data show that genetic modifiers can impact beta cell regulation of retinoic acid signalling and circadian entrainment to modulate beta cell ageing and disease penetrance in mice modelling MAFA -MODY. Data availability Sequencing data were deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (accession no. GSE299343 for bulk RNA-seq and GSE298664 for CUT&RUN analyses).