Fig. 5.

Pharmacological inhibition of EZH2 catalyses pancreatic progenitor activation and β-cell maturation. The schematic outlines the progression from pancreatic multipotent progenitors to mature insulin-secreting β-cells, highlighting the regulatory target of EZH2 inhibitors, GSK126 and Tazemetostat. These progenitors, originating in the Islets of Langerhans’ pancreatic ducts, are maintained in a multipotent state post-development associated with EZH2-mediated suppression with H3K27me3 content enriched on endocrine genes. Reducing H3K27me3 levels shifts bivalent H3K4me3 mark on these progenitors towards the endocrine lineage, marked by PTF1A activation and primes these cells for β-cell differentiation. While FGF10 signalling stabilises this progenitor state, ISL1 and NEUROD1 influence endocrine commitment that support β-cell maturation. Upregulation of GPR119 and IAPP, along with the downregulation of ADRA2C, weakens inhibitory signals, facilitating glucose-stimulated insulin secretion