Epigenetics: deciphering its role in diabetes and its chronic complications

Abstract

1. Increasing evidence suggests that epigenetic factors might regulate the complex interplay between genes and the environment, and affect human diseases, such as diabetes and its complications. 2. Clinical trials have underscored the long lasting beneficial effects of strict glycaemic control for reducing the progression of diabetic complications. They have also shown that diabetic complications, such as diabetic nephropathy, a chronic kidney disorder, can continue even after blood glucose normalization, suggesting a metabolic memory of the prior glycaemic state. 3. Dysregulation of epigenetic post-transcriptional modifications of histones in chromatin, including histone lysine methylation, has been implicated in aberrant gene regulation associated with the pathology of diabetes and its complications. Genome-wide studies have shown cell-type specific changes in histone methylation patterns under diabetic conditions. In addition, studies in vascular cells have shown long lasting changes in epigenetic modifications at key inflammatory gene promoters after prior exposure to diabetic conditions, suggesting a possible mechanism for metabolic memory. 4. Recent studies have shown roles for histone methylation, DNA methylation, as well as microRNA in diabetic nephropathy. Whether these epigenetic factors play a role in metabolic memory of diabetic kidney disease is less well understood. 5. The incidence of diabetes is growing rapidly, as also the cost of treating the resulting complications. A better understanding of metabolic memory and the potential involvement of epigenetic mechanisms in this phenomenon could enable the development of new therapeutic targets for the treatment and/or prevention of sustained diabetic complications.

Figure 1. Metabolic Memory and Diabetic Complications

In the Diabetes Control and Complications Trial (DCCT) conducted from 1983-1993, Type 1 Diabetic patients were placed either on conventional or intensive insulin treatment for an average of 6.5 years. At the end of the study, patients on intensive control have reduced microvascular complications relative to the conventional group. In the follow up Epidemiology of Diabetes Interventions and Complications (EDIC) trial (1993 to date), both groups of patients were placed under intensive control regimen. EDIC study showed that patients previously in the DCCT conventional treatment group were still at a greater risk for vascular complications compared to those on intensive control in DCCT. These long lasting effects have been suggested to be due to a ‘Metabolic Memory’ of prior hyperglycemic exposure.

Figure 2. Model of epigenetic regulation of gene expression associated with diabetic complications

Post translational modifications of N-terminal histone tails play essential roles in gene regulation and are regulated by various chromatin modifiers. Tri-methylation of histone H3 lysine 9 and lysine 27 are usually associated with repression, while methylation of histone H3 lysine 4 and acetylation at lysine 9 are both associated with gene activation. In the schematic model shown, diabetic conditions such as hyperglycemia lead to a loss of repressive modifications that normally maintain regulated control of gene expression, while activating histone modifications may be increased, thus leading to relaxation or opening of the chromatin structure around key pathologic genes resulting in increased transcription. Various combinations of histone modifications mediated by several HMTs are likely to be involved. 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.

Fig. 3. Metabolic Memory and epigenetic mechanisms for diabetic complications

Diabetes, Hyperglycemia and AGEs activate multiple signal transduction pathways including oxidative stress, which regulate of transcription factors (TFs), and epigenetic factors such as Histone methyl transferases (HMTs), Histone acetyl transferases (HATs) and DNA methyl transferases (DNMTs) to alter histone posttranslational modifications (Histone PTMs) and DNA methylation (DNA-me) at promoters of inflammatory and extracellular matrix (ECM) genes (such as MCP-1, IL-6, TGF-beta, PAI-1 and Collagen) leading to changes in their expression. Histone deacetylases (HDACs) and lysine demethylases (KDMs) are also likely to be involved in the regulation of Histone PTMs (not shown). Persistence of these epigenetic marks at target gene regions may be a major mechanism for ‘Metabolic Memory’ implicated in the continued development of vascular and renal complications despite glucose control.