FoxM1 coordinates cell division, protein synthesis, and mitochondrial activity in a subset of cells during acute metabolic stress

Pancreatic beta cells display functional and transcriptional heterogeneity in health and disease. The sequence of events leading to beta cell heterogeneity during metabolic stress is poorly understood. Here, we characterize beta cell responses to early metabolic stress in vivo by employing RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA-seq (scRNA-seq), chromatin immunoprecipitation sequencing (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 demonstrate that a subpopulation of beta cells with active UPR, decreased protein synthesis, and insulin secretary capacities is more susceptible to proliferation after insulin depletion. Alleviation of endoplasmic reticulum (ER) stress precedes the progression of the 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 beta cells by regulating protein synthesis, ER stress, and mitochondrial activity via direct repression of mitochondrial-encoded genes.