| First Author | Jetton TL | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 5 | Pages | 101250 |
| PubMed ID | 34592314 | Mgi Jnum | J:312782 |
| Mgi Id | MGI:6787305 | Doi | 10.1016/j.jbc.2021.101250 |
| Citation | Jetton TL, et al. (2021) SetD7 (Set7/9) is a novel target of PPARgamma that promotes the adaptive pancreatic beta-cell glycemic response. J Biol Chem 297(5):101250 |
| abstractText | Loss of functional pancreatic beta-cell mass leads to type 2 diabetes (T2D), attributable to modified beta-cell-dependent adaptive gene expression patterns. SetD7 is a histone methyltransferase enriched in pancreatic islets that mono- and dimethylates histone-3-lysine-4 (H3K4), promoting euchromatin modifications, and also maintains the regulation of key beta-cell function and survival genes. However, the transcriptional regulation of this important epigenetic modifier is unresolved. Here we identified the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) as a major transcriptional regulator of SetD7 and provide evidence for direct binding and functionality of PPARgamma in the SetD7 promoter region. Furthermore, constitutive shRNA-mediated PPARgamma knockdown in INS-1 beta-cells or pancreas-specific PPARgamma deletion in mice led to downregulation of SetD7 expression as well as its nuclear enrichment. The relevance of the SetD7-PPARgamma interaction in beta-cell adaptation was tested in normoglycemic 60% partial pancreatectomy (Px) and hyperglycemic 90% Px rat models. Whereas a synergistic increase in islet PPARgamma and SetD7 expression was observed upon glycemic adaptation post-60% Px, in hyperglycemic 90% Px rats, islet PPARgamma, and PPARgamma targets SetD7 and Pdx1 were downregulated. PPARgamma agonist pioglitazone treatment in 90% Px rats partially restored glucose homeostasis and beta-cell mass and enhanced expression of SetD7 and Pdx1. Collectively, these data provide evidence that the SetD7-PPARgamma interaction serves as an important element of the adaptive beta-cell response. |
