The promoter of
MMP-9 has many transcriptional factor binding sites,
9 and the binding of transcriptional factors AP-1 and nuclear factor-
kB (NF-
kB) is increased at the retinal
MMP-9 promoter in diabetes.
10,11 In addition to transcription factors, epigenetic modifications including DNA methylation and histone modifications, can also regulate the gene expression without altering the DNA sequence, and the same gene can be regulated by multiple epigenetic modifications.
12,13 We have shown that in diabetes, lysine 9 of histone 3 (H3K9) of retinal
MMP-9 promoter is hyperacetylated, facilitating the binding of NF-
kB.
11 Histone 3, however, can undergo at least 17 different posttranslational modifications, and methylation is one of the most abundant modifications, which is mainly considered as a gene repressive mark.
14 Trimethylation of lysine 27 of histone 3 (H3K27me3) is a relatively stable inheritable repressive histone mark and enhancer of Zeste homolog 2 (Ezh2), the catalytic component of the polycomb repressive complex 2 (PRC2) histone methyltransferase, catalyzes dimethylation (me2) and trimethylation (me3) of H3K27, repressing the expression of many target genes including
MMP-9.
15,16 Ezh2 expression is increased in retinal endothelial cells in diabetes,
17 but, its role in regulating
MMP-9 expression remains unclear. Ezh2 is also directly involved in DNA methylation,
18,19 and in diabetes
MMP-9 promoter undergoes dynamic DNA methylation. Despite increased recruitment of DNA methyltransferase 1 (Dnmt1) at the
MMP-9 promoter in diabetes, our results have shown that 5 methyl cytosine (5mC) levels are decreased. The reason for the decrease in 5mC appears to be the concomitant increase in the binding of hydroxymethylase, ten-eleven translocase 2 (Tet2), at the same site of the promoter, and increase in 5 hydroxymethyl cytosine (5hmC), in turn, activates
MMP-9 transcription.
20 However, the crosstalk between histone methylation and DNA methylation in the regulation of retinal
MMP-9 in diabetes remains to be investigated.