Genetic background modulates MafAS64F-mediated islet ageing in male mice.

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 (MafAS64F) produces an unusually long-lived variant protein that predisposes male carriers to MODY. Here we investigated how genetic background modulates disease penetrance in MafaS64F/+ male mice.

METHODS

MafaS64F/+ 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 MafaS64F/+ 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

MafaS64F/+ 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 MafaS64F/+ male mice, comparable with control littermates. RNA-seq of C57BL/6J MafaS64F/+ male mouse islets revealed relative normalisation of DEGs associated with cellular ageing and circadian regulation. In addition, islets from C57BL/6J MafaS64F/+ 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 MafaS64F/+ 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).