| First Author | Maganti AV | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 15 | Pages | 9812-22 |
| PubMed ID | 25713082 | Mgi Jnum | J:338772 |
| Mgi Id | MGI:6832290 | Doi | 10.1074/jbc.M114.616219 |
| Citation | Maganti AV, et al. (2015) Transcriptional activity of the islet beta cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9. J Biol Chem 290(15):9812-22 |
| abstractText | The transcription factor Pdx1 is crucial to islet beta cell function and regulates target genes in part through interaction with coregulatory factors. Set7/9 is a Lys methyltransferase that interacts with Pdx1. Here we tested the hypothesis that Lys methylation of Pdx1 by Set7/9 augments Pdx1 transcriptional activity. Using mass spectrometry and mutational analysis of purified proteins, we found that Set7/9 methylates the N-terminal residues Lys-123 and Lys-131 of Pdx1. Methylation of these residues occurred only in the context of intact, full-length Pdx1, suggesting a specific requirement of secondary and/or tertiary structural elements for catalysis by Set7/9. Immunoprecipitation assays and mass spectrometric analysis using beta cells verified Lys methylation of endogenous Pdx1. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed a requirement of Pdx1 residue Lys-131, but not Lys-123, for transcriptional augmentation by Set7/9. Lys-131 was not required for high-affinity interactions with DNA in vitro, suggesting that its methylation likely enhances post-DNA binding events. To define the role of Set7/9 in beta cell function, we generated mutant mice in which the gene encoding Set7/9 was conditionally deleted in beta cells (Set(Delta)beta). Set(Delta)beta mice exhibited glucose intolerance similar to Pdx1-deficient mice, and their isolated islets showed impaired glucose-stimulated insulin secretion with reductions in expression of Pdx1 target genes. Our results suggest a previously unappreciated role for Set7/9-mediated methylation in the maintenance of Pdx1 activity and beta cell function. |
