Fig. 3.
Scheme for the role of epigenetic mechanisms downstream of hyperglycemia in leading to diabetic complications. Diabetic conditions or hyperglycemia can activate several signal transduction pathways and transcription factors that can lead to sustained expression of pathological genes in the nucleus by cooperating with epigenetic factors. This can occur via a loss of repression and a corresponding gain in activation pathways, leading to long-lasting epigenetic changes through gene promoter histone lysine modifications near key transcription factor binding sites or other important chromatin regions. Depending on the specific lysine residue that is methylated, histone lysine methylation is associated with either gene activation (H3K4me) or repression (H3K9me). Modifications at other lysine residues may also be involved. These associations are further complicated by the gene location modified, either promoter or coding region, and the degree of methylation, all of which can affect accessibility of chromatin and transcriptional outcomes. These epigenetic modifications can be maintained through cell division via mechanisms that are not yet clearly understood but may include DNA methylation as well as transmission of histone lysine methylation marks. The persistence of these epigenetic changes might explain the metabolic memory phenomenon responsible for the continued development of diabetic complication even after glucose control has been achieved.