Diabetes induces tri-methylation at lysine 9 of histone 3 at Slc2a4 gene in skeletal muscle: A new target to improve glycemic control

Expression of the glucose transporter GLUT4, encoded by Slc2a4 gene, is reduced in both type 1 and type 2 diabetes (T1D and T2D), contributing to glycemic impairment. The present study investigated epigenetic regulations at the Slc2a4 promoter in skeletal muscle of T1D- and T2D-like experimental models. Slc2a4/GLUT4 repression was observed in T1D and T2D and that was reversed by insulin and resveratrol treatments, respectively. In both T1D-like and T2D-like animals, tri-methylation at lysine 9 of histone 3 (H3K9me3) increased in the Slc2a4 enhancer segment, whereas MEF2A/D binding into this segment was reduced; all effects were reversed by respective treatments. This study reveals that increased H3K9me3 in the Slc2a4 promoter enhancer segment contributes to reduce GLUT4 expression in skeletal muscle and to worse glycemic control in diabetes, pointing to the H3K9me3 of Slc2a4 promoter as a potential target for development of new approaches for treating diabetes. •T1D and TD2 repress Slc2a4/GLUT4 expression in murine skeletal muscle.•T1D and T2D increase H3K9me3 of the enhancer segment of the Slc2a4 promoter gene.•Increased H3K9me3 impairs the binding activity of MEF2A/D in the Slc2a4 promoter.•T1D- and T2D-induced Slc2a4 H3K9me reverses by insulin and resveratrol, respectively.