SetD7 (Set7/9) is a novel target of PPARγ that promotes the adaptive pancreatic β-cell glycemic response

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 (PPAR gamma) as a major transcriptional regulator of SetD7 and provide evidence for direct binding and functionality of PPAR gamma in the SetD7 promoter region. Furthermore, constitutive shRNA-mediated PPAR gamma knockdown in INS-1 beta-cells or pancreas-specific PPAR gamma deletion in mice led to downregulation of SetD7 expression as well as its nuclear enrichment. The relevance of the SetD7-PPAR gamma 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 PPAR gamma and SetD7 expression was observed upon glycemic adaptation post-60% Px, in hyperglycemic 90% Px rats, islet PPAR gamma, and PPAR gamma targets SetD7 and Pdx1 were downregulated. PPAR gamma 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-PPAR gamma interaction serves as an important element of the adaptive beta-cell response.