Di-methylation of histone H3 lysine (K) 4, a component of the epigenetic memory, is associated with gene transactivation. In this study, we examined whether the development of diabetes induces di-methylation of histone H3 1(4 on the upregulated genes. We searched for upregulated genes in mesenteric adipose tissue of insulin-resistant/diabetic db/db mice compared with non-diabetic db/m mice using microarray analysis. We also performed chromatin immunoprecipitation assays for di-methylation of histone H3 1(4 in the upregulated genes in mesenteric adipose tissue of db/m and db/db mice. Di-methylation of histone H3 K4 was enhanced at the upstream and/or transcribed regions of upregulated genes including Atp6v0d2, Mmp12, Trem2 and Clec4d genes in mesenteric adipose tissue of db/db mice, as compared with db/m mice. These results suggest that di-methylation of histone H3 1(4 is involved in the induction of Atp6v0d2, Mmp12, Trem2 and Clec4d in mesenteric adipose tissue in db/db mice. (C) 2010 Elsevier Inc. All rights reserved.