High-resolution temporal analysis of β-cells reveals role of FoxM1 in protein synthesis and mitochondrial activity during metabolic stress

Pancreatic β-cells display functional and transcriptional heterogeneity in health and disease. The sequence of events leading to β-cell heterogeneity during metabolic stress is poorly understood. We have characterized β-cell responses to early metabolic stress in vivo by employing RNA-seq, ATAC-seq, scRNA-seq, ChIP-seq and real-time imaging to decipher temporal events of chromatin remodeling and gene expression regulating the unfolded protein response (UPR), protein synthesis, mitochondrial function and cell cycle progression. We demonstrated that a subpopulation of β-cells with active UPR, increased protein synthesis and insulin secretary capacities is more susceptible to proliferate after insulin depletion. Alleviation of ER stress precedes the progression of cell cycle and mitosis and ensures appropriate insulin synthesis. Furthermore, metabolic stress rapidly activates key transcription factors including FoxM1, which impacts on proliferative and quiescent β-cells through previously unrecognized functions in regulating protein synthesis, ER stress and mitochondrial activity via direct repression of mitochondrial encoded genes.