In the development of diabetic retinopathy, superoxide radicals are elevated in the retinal mitochondria and their scavenging enzyme, MnSOD, is compromised. We are investigating how MnSOD gene (sod2) is epigenetically regulated in the pathogenesis of diabetic retinopathy. Our studies have shown that diabetes modifies retinal sod2 by increasing H4K20me3 at its promoter, and this downregulates the enzyme. Our hope is that by better understanding the epigenetic approaches useful markers for disease diagnostics can be revealed, and regulation of such changes by pharmaceutical or molecular means could provide a potential strategy to retard the development of diabetic retinopathy.