Islet-1 Is Essential for Pancreatic β-Cell Function

Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal beta-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, beta-cell-specific Isl-1 loss-of-function mouse: Isl-1(L/L); Pdx1-CreER(Tm). Ablating Isl-1 in postnatal beta-cells reduced glucose tolerance without significantly reducing beta-cell mass or increasing beta-cell apoptosis. Rather, islets from Isl-1(L/L); Pdx1-CreER(Tm) mice showed impaired insulin secretion. To identify direct targets of Isl-1, we integrated high-throughput gene expression and Isl-1 chromatin occupancy using islets from Isl-1(L/L); Pdx1-CreER(Tm) mice and beta TC3 insulinoma cells, respectively. Ablating Isl-1 significantly affected the beta-cell transcriptome, including known targets Insulin and MafA as well as novel targets Pdx1 and Slc2a2. Using chromatin immunoprecipitation sequencing and luciferase reporter assays, we found that Isl-1 directly occupies functional regulatory elements of Pdx1 and Slc2a2. Thus Isl-1 is essential for postnatal beta-cell function, directly regulates Pdx1 and Slc2a2, and has a mature beta-cell cistrome distinct from that of pancreatic endocrine progenitors.