Transcriptional Activity of the Islet β Cell Factor Pdx1 is Augmented by Lysine Methylation Catalyzed by the Methyltransferase Set7/9
dc.contributor.author | Maganti, Aarthi V. | |
dc.contributor.author | Maier, Bernhard | |
dc.contributor.author | Tersey, Sarah A. | |
dc.contributor.author | Sampley, Megan L. | |
dc.contributor.author | Mosley, Amber L. | |
dc.contributor.author | Özcan, Sabire | |
dc.contributor.author | Pachaiyappan, Boobalan | |
dc.contributor.author | Woster, Patrick M. | |
dc.contributor.author | Hunter, Chad S. | |
dc.contributor.author | Stein, Roland | |
dc.contributor.author | Mirmira, Raghavendra G. | |
dc.contributor.department | Department of Cellular & Integrative Physiology, IU School of Medicine | en_US |
dc.date.accessioned | 2015-08-05T16:14:21Z | |
dc.date.available | 2015-08-05T16:14:21Z | |
dc.date.issued | 2015-04 | |
dc.description.abstract | The transcription factor Pdx1 is crucial to islet β 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 β 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 β cell function, we generated mutant mice in which the gene encoding Set7/9 was conditionally deleted in β cells (SetΔβ). SetΔβ 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 β cell function. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Maganti, A. V., Maier, B., Tersey, S. A., Sampley, M. L., Mosley, A. L., Özcan, S., ... & Mirmira, R. G. (2015). Transcriptional Activity of the Islet β Cell Factor Pdx1 Is Augmented by Lysine Methylation Catalyzed by the Methyltransferase Set7/9. Journal of Biological Chemistry, 290(15), 9812-9822. | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/6616 | |
dc.language.iso | en_US | en_US |
dc.relation.isversionof | 10.1074/jbc.M114.616219 | en_US |
dc.relation.journal | Journal of Biological Chemistry | en_US |
dc.rights | IUPUI Open Access Policy | en_US |
dc.source | Publisher | en_US |
dc.subject | pancreatic islet | en_US |
dc.subject | protein methylation | en_US |
dc.subject | diabetes | en_US |
dc.subject | gene knockout | en_US |
dc.title | Transcriptional Activity of the Islet β Cell Factor Pdx1 is Augmented by Lysine Methylation Catalyzed by the Methyltransferase Set7/9 | en_US |
dc.type | Article | en_US |