Figure 1. Transcriptional regulation in the pancreatic β cell.

(A) Schematic overview of a pancreatic β cell. The endocrine cells perform glucose-stimulated insulin secretion, which consists of a signaling cascade including glucose uptake via the glucose transporter GLUT2, glucose metabolism and ATP production during glycolysis, ATP-induced blocking of K_ATP channels, depolarization of the cell membrane, opening of voltage-gated calcium channels (VGCC), and the calcium-induced exocytosis of insulin granules. Differentiated pancreatic β cells are controlled by a complex gene regulatory network, including the transcription factors HNF-1A, HNF-4A, FOXA2/3, pancreatic and duodenal homeobox 1 (PDX1), and paired box protein Pax-6 (PAX6), which together regulate target genes such as insulin (INS), glucokinase (GCK), and GLUT2. Sizes not to scale. (B) HNF-1A:HNF-4A regulatory circuit, in which each factor regulates the other by transcriptional control and protein-protein interactions. Boxes represent HNF1A and HNF4A genes, and triangles represent translated HNF-1A and HNF-4A proteins. Arrows indicate transcriptional control. (C) Domain overview of HNF-1A (top) and HNF-4A (bottom). DD, dimerization domain; DBD, DNA binding domain; POU_S, POU-specific domain; POU_H, POU homeodomain; TAD, transactivation domain; AF, activation function domain; H, hinge region; LBD, ligand binding domain; F, F domain; A/B, A/B domain (36, 69, 70). (D) Architecture and sequence conservation of the P2-HNF4A promoter, including transcription factor binding sites for HNF-1, PDX1, and HNF-6. Figure inspired by refs. 24, 32, and 52.