Elsevier

Biochemical Pharmacology

Volume 80, Issue 12, 15 December 2010, Pages 1853-1859
Biochemical Pharmacology

Review
Glycemic memory associated epigenetic changes

https://doi.org/10.1016/j.bcp.2010.06.005Get rights and content

Abstract

It is evident that metabolic memory, whereby diabetic complications continue to develop and progress in individuals who returned to normal glycemic control after a period of transient hyperglycemia, can have long lasting effects. We have primary findings that transient hyperglycemia causes profound transcriptional changes in vascular endothelial cells. We hypothesized that ambient hyperglycemia triggers gene-activating events of the NFκB p65 promoter that are mediated by changes in epigenetic modifications. In a follow-up study we identified two histone-specific writing and erasing enzymes involved in the underlying regulation of gene expression during transient hyperglycemia and subsequent return to normoglycemia. Experimental evidence indicates that previous hyperglycemia is associated with persistent expression of the NFκB p65 gene, which activates NFκB-dependent proteins, such as MCP-1, which are implicated in diabetes-associated vascular injury. Increased gene transcription is correspondent with H3K4m1, but not H3K4m2 and H3K4m3, on the NFκB p65 gene. In vascular endothelial cells the histone methyltransferase Set7 can write the mono-methylation mark H3K4m1 and this methyl-writing enzyme is recruited as a gene co-activator in response to glucose. Furthermore, Set7 knockdown prevents glucose-induced p65 expression. We hypothesize that these molecular events represent an integrated response of the epigenome that lead to changes in the expression of genes and proteins that regulate the development and progression of diabetic vascular complications. Further characterisation of these glucose-induced epigenetic events and the identification of key enzymes involved will improve our understanding of the pathways implicated in diabetic vascular injury.

Section snippets

Glycemic variability and diabetic complications

Cardiovascular complications remain the major cause of morbidity and mortality in the diabetic population [1]. Patients with type 1 or type 2 diabetes have a two- to four-fold higher risk of cardiovascular disease when compared to healthy individuals [2], [3], and those with impaired glucose tolerance alone have a cardiovascular disease risk comparable to type 2 diabetics [4]. It is increasingly appreciated that exposure to high glucose is the major factor leading to these complications.

Studying epigenetic changes

Epigenetics describes the study of heritable changes in gene activity and expression independent of changes in nucleotide sequence [16]. These epigenetic changes are potentially reversible and modulated by the environment, diet or pharmacological intervention (Fig. 2). This in turn can mediate changes in genomic stability and gene expression [17], [18], [19]. Essentially the field of epigenetics provides a link between genotype and phenotype, which can help explain how cells carrying identical

Nutritional intervention and epigenetic modifications

Many studies have examined links between obesity, energy metabolism, nutrient balance and epigenetic modifications [34], [35], [36], [37], [38]. Obesity is associated with loss of function of the histone demethylase, Jhdm2a, resulting in decreased expression of the metabolically active gene peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in skeletal muscle and impaired uncoupling protein 1 expression in brown adipose tissue suggesting a relationship between epigenetic mechanisms

Epigenetic regulation of diabetic complications

Oxidative stress, dyslipidemia and hyperglycemia are thought to be associated with the development of diabetic complications. The major event in the progression of diabetic complications is vascular inflammation, triggered by a pathway of mediators to enhance inflammatory signalling. Nuclear factor-κB (NFκB) is one of the predominant transcription factors that are activated under diabetic conditions in the inflammatory pathway, leading to recruitment of monocytes and macrophages to the vessel

The role of histone-modifying enzymes in glycemic variability

Currently there is intensive research into the identification and characterisation of the enzymes that control and direct histone modifications [54], [55], of which the methyltransferases are most specific. Lysine methyltransferases have enormous specificity compared to acetyltransferases, usually modifying one single lysine on the histone tail [17], [56]. The existence of lysine demethylases remained contentious for many years following the discovery of histone methyltransferases (HMTase). The

The current landscape and perspectives—where to next?

Investigators in our laboratory are interested in examining the dynamic state of epigenetic changes in response to environmental stimuli. Specifically, hyperglycemia and the persistence of epigenetic phenomena are a primary focus of some of the research currently investigated. In fact, many researchers are attempting to unravel the molecular determinants associated with recognizing the chromatin template and regulate the histone code. Understanding the exact changes in histone methylation, the

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