The role of epigenetics in the pathology of diabetic complications

Abstract

Diabetes is associated with significantly accelerated rates of several debilitating microvascular complications such as nephropathy, retinopathy, and neuropathy, and macrovascular complications such as atherosclerosis and stroke. While several studies have been devoted to the evaluation of genetic factors related to type 1 and type 2 diabetes and associated complications, much less is known about epigenetic changes that occur without alterations in the DNA sequence. Environmental factors and nutrition have been implicated in diabetes and can also affect epigenetic states. Exciting research has shown that epigenetic changes in chromatin can affect gene transcription in response to environmental stimuli, and changes in key chromatin histone methylation patterns have been noted under diabetic conditions. Reports also suggest that epigenetics may be involved in the phenomenon of metabolic memory observed in clinic trials and animal studies. Further exploration into epigenetic mechanisms can yield new insights into the pathogenesis of diabetes and its complications and uncover potential therapeutic targets and treatment options to prevent the continued development of diabetic complications even after glucose control has been achieved.

Fig. 1.

Hyperglycemia-induced activation of molecular pathways associated with diabetic complications. Diabetes and associated hyperglycemia can lead to increased activation of PKC, MAPKs, and downstream signaling, production of reactive oxygen species (ROS) and reactive nitrative species (RNS), and formation of advanced glycation end products (AGE) and signaling through the receptor for AGE (RAGE). Each of these events can lead to production and increased action of various growth factors such as ANG II and transforming growth factor-β (TGF-β) and activation of transcription factors such as NF-κB, changes in histone methylation (histone-me) patterns, and altered DNA methylation (DNA-me) at various genes in target cells, all of which over time can result in changes to the expression patterns of inflammatory, sclerotic, and other pathological genes and the ultimate development of diabetic complications.

Fig. 2.

Model for epigenetic regulation of pathological gene expression in diabetes via changes in chromatin histone modifications. Posttranslational modifications on the N-terminal histone tails in chromatin play essential roles in gene regulation and are regulated by various chromatin modifiers. Histone lysine methyltransferases (HMTs) and lysine demethylases (KDMs) regulate histone lysine methylation (Kme), while histone acetyltransferases (HATs) and histone deacetylases (HDACs) control histone acetylation (Ac). In the proposed model shown, various chromatin modifiers maintain sufficient levels of repressive histone marks to maintain strict control of pathological gene expression under normal conditions; these would include methylation of H3K9 and demethylation of H3K4 in addition to deacetylation by HDACs. However, under diabetic conditions, including hyperglycemia, the negative regulators such as H3K9 methylation marks of repressed chromatin would be lost, while positive regulators or activating histone marks such as H3K4 methylation and histone acetylation may be increased, thus leading to relaxation or opening of the chromatin structure around key pathological genes to increase their transcription. Various combinations of histone modifications are likely to be involved.

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.