Bromodomain and Extra Terminal Proteins Inhibitors Promote Pancreatic Endocrine Cell Fate.

Bromodomain and Extra-terminal (BET) proteins are epigenetic readers that interact with acetylated lysines of histone tails. Recent studies have demonstrated their role in cancer progression, as they recruit key components of the transcriptional machinery to modulate gene expression. However, their role during embryonic development of the pancreas has never been studied. Using mouse embryonic pancreatic explants and hiPSCs, we show that BET proteins inhibition with I-BET151 or JQ1 enhances the number of neurogenin3 endocrine progenitors. In mouse explants, BET proteins inhibition further led to increased expression of β cell markers, but in the meantime strongly downregulated Ins1 expression. Similarly, while acinar markers, such as Cpa1 and CelA were upregulated, Amy expression was repressed. In hiPSCs, BETi strongly repressed C-PEP and GCG during endocrine differentiation. Explants and hiPSCs were then pulsed with BETi to increase NEUROG3 expression, and further chased without inhibitors. Endocrine development was enhanced in explants, with higher expression of insulin and maturation markers, such as UCN3 and MAFA. In hiPSC, the outcome was different, as C-PEPTIDE expression remained lower than in control, but Ghrelin expression was increased. Altogether, by using two independent models of pancreatic development, we show that BET proteins regulate multiple aspects of pancreas development.