Abstract:
The Set7 lysine methyltransferase catalyses mono-methylation of the histone H3 on lysine residue 4 (H3K4me1) and has previously been shown to regulate gene expression. The role of Set7 in diabetic endothelial dysfunction remains poorly understood.
In this study, we examine the influence of Set7 on the expression of genes implicated in diabetes. RNA expression was assessed using a Set7 knock-out animal model and a specific pharmacological inhibitor of the enzyme. Gene set enrichment analysis of RNA sequencing data showed changes in pro-inflammatory gene expression in diabetic complications. To extend our in vivo findings, we examined the pharmacological inhibition of Set7 in cultured human microvascular endothelial cells (HMEC-1) using (R)-PFI-2 and TNF. Set7-dependent gene expression was analysed by chromatin immunoprecipitation (ChIP) to determine H3K4me1 at gene targets associated with diabetic endothelial dysfunction.
In response to Set7 inhibition, RNA-seq analysis indicated significant differential expression of genes previously shown to be implicated in endothelial dysfunction. We show that H3K4me1 patterns on the selected gene VCAM1 were reduced using the Set7 inhibitor, (R)-PFI-2, which is consistent with its gene suppression. Assessment of multiple genomic regions along VCAM1 revealed a possibly critical region, upstream of the promoter, which was influenced by (R)-PFI-2. In conclusion, Set7 is an epigenetic regulator that is involved in diabetic pathways, as characterized by its regulation of genes implicated in endothelial dysfunction. While further validation of these findings is required, we consider that targeting Set7 may have therapeutic potential in management of diabetes and its complications.
