Transcriptional Activity of the Islet β Cell Factor Pdx1 Is Augmented by Lysine Methylation Catalyzed by the Methyltransferase Set7/9

Abstract

Background: Pdx1 interacts with the methyltransferase Set7/9 to transactivate ␤ cell genes. Results: Methylation of Pdx1 residue Lys-131 by Set7/9 augments Pdx1 activity. Conclusion:The ability of Pdx1 to regulate genes in ␤ cells is partially dependent upon its methylation by Set7/9. Significance: This study reveals a previously unappreciated role for Lys methylation in the maintenance of Pdx1 activity and ␤ cell function.

The histone methyltransferase Setd7 promotes pancreatic progenitor identity

“…In this study, specific ablation of Setd7 in adult pancreatic β-cells results in glucose intolerance and β-cell dysfunction that is reminiscent of Pdx1 heterozygous mouse mutation and parallels previous in vitro observations in isolated islets (Brissova et al, 2002;Deering et al, 2009;Maganti et al, 2015). Importantly, these findings suggest a late role for Setd7 in the maintenance of key Pdx1 target genes and Pdx1 itself (Maganti et al, 2015); whether Pdx1 is also dependent upon the action of Setd7 at earlier stages in the mouse developing pancreas, as we observed in the Xenopus, deserves further investigation. Interestingly, upon depletion of Setd7 in the frog endoderm, the reduction of pancreatic gene expression appears concomitant with changes in regional gene expression of well-known gut markers, such as sox2, and of some gut-type mesoderm, marked by tbx5 (Chalmers and Slack, 2000;Horb and Slack, 2001), suggesting a broader role for Setd7 in regional specification and patterning of the endoderm.…”

“…In addition, there are overall major discrepancies among the phenotypes reported in these three different Setd7 mouse models (Campaner et al, 2011;Kurash et al, 2008;Lehnertz et al, 2011) that might be due to differences in the mouse genetic background or targeting strategies used. More recently, a tamoxifen-inducible β-cell-specific Setd7 knockout mouse was established using a gene targeting strategy that was different to those used before (Maganti et al, 2015). In this study, specific ablation of Setd7 in adult pancreatic β-cells results in glucose intolerance and β-cell dysfunction that is reminiscent of Pdx1 heterozygous mouse mutation and parallels previous in vitro observations in isolated islets (Brissova et al, 2002;Deering et al, 2009;Maganti et al, 2015).…”

“…For instance, Setd7 appears to function synergistically with Smyd3, a KMT that uses H3K4me1 and H3K4me2 as substrate to establish H3K4me3, during heart development in zebrafish (Kim et al, 2015). On the other hand, other studies associated Setd7 itself with the establishment of di-and tri-methylation (Dhayalan et al, 2011;Francis et al, 2005;Maganti et al, 2015). Finally, acetylation of H3K27 by p300 is facilitated by Setd7-mediated H3K4 methylation (Wang et al, 2001), which might explain the observed reduction of H3K27ac upon setd7-MO knockdown.…”

“…More recently, a tamoxifen-inducible β-cell-specific Setd7 knockout mouse was established using a gene targeting strategy that was different to those used before (Maganti et al, 2015). In this study, specific ablation of Setd7 in adult pancreatic β-cells results in glucose intolerance and β-cell dysfunction that is reminiscent of Pdx1 heterozygous mouse mutation and parallels previous in vitro observations in isolated islets (Brissova et al, 2002;Deering et al, 2009;Maganti et al, 2015). Importantly, these findings suggest a late role for Setd7 in the maintenance of key Pdx1 target genes and Pdx1 itself (Maganti et al, 2015); whether Pdx1 is also dependent upon the action of Setd7 at earlier stages in the mouse developing pancreas, as we observed in the Xenopus, deserves further investigation.…”

“…In adult mammalian pancreatic islets, Setd7 is recruited to a complex with Pdx1 to mediate histone H3 methylation at the insulin gene promoter and recruitment of RNA polymerase II (Deering et al, 2009;Francis et al, 2005), suggesting an important role in normal β-cell function. Despite these diverse substrates and very broad targets, Setd7 knockout mouse models have no obvious developmental defects and the exact in vivo function of Setd7 remains largely undetermined (Campaner et al, 2011;Kurash et al, 2008;Lehnertz et al, 2011;Maganti et al, 2015).…”