BRD4 signaling maintains the differentiated state of β cells [scRNA-seq]

In diabetes, pancreatic β cells degenerate from their mature differentiated state to a dedifferentiated state. BRD4 plays a pivotal role during embryogenesis and cancer development, but its function in modulating β-cell differentiation remains unknown. In this study, multiple models including calorie restriction db/db mouse, long-term and acute conditional knockout mouse and human islet organoids were adopted to assess BRD4 function in β cells. 222 young patients with diabetes were also recruited for whole exome sequencing (WES) to screen for BRD4 mutations. Our study showed that BRD4 expression was significantly reduced in human diabetic β cells while significantly increased after calorie restriction in the diabetic mouse. β cell differentiation was impaired after long-term and acute Brd4 knockout. BRD4 knockdown in human islet organoids results in the loss of differentiation and reduction of insulin synthesis. We found that p.R749C can significantly affect BRD4 signaling and might be a causative mutation contributing to diabetes development in patients. Our study also showed that ATF5 is a direct target of the BRD4 pathway in β cells. Targeting BRD4-mediated regulatory networks may hold promise for developing novel therapeutic strategies to maintain the differentiated state of β cells.