Epigenetic mechanisms in diabetic complications and metabolic memory

Abstract

The incidence of diabetes and its associated micro- and macrovascular complications is greatly increasing worldwide. The most prevalent vascular complications of both type 1 and type 2 diabetes include nephropathy, retinopathy, neuropathy and cardiovascular diseases. Evidence suggests that both genetic and environmental factors are involved in these pathologies. Clinical trials have underscored the beneficial effects of intensive glycaemic control for preventing the progression of complications. Accumulating evidence suggests a key role for epigenetic mechanisms such as DNA methylation, histone post-translational modifications in chromatin, and non-coding RNAs in the complex interplay between genes and the environment. Factors associated with the pathology of diabetic complications, including hyperglycaemia, growth factors, oxidant stress and inflammatory factors can lead to dysregulation of these epigenetic mechanisms to alter the expression of pathological genes in target cells such as endothelial, vascular smooth muscle, retinal and cardiac cells, without changes in the underlying DNA sequence. Furthermore, long-term persistence of these alterations to the epigenome may be a key mechanism underlying the phenomenon of 'metabolic memory' and sustained vascular dysfunction despite attainment of glycaemic control. Current therapies for most diabetic complications have not been fully efficacious, and hence a study of epigenetic mechanisms that may be involved is clearly warranted as they can not only shed novel new insights into the pathology of diabetic complications, but also lead to the identification of much needed new drug targets. In this review, we highlight the emerging role of epigenetics and epigenomics in the vascular complications of diabetes and metabolic memory.

Fig. 1

Signalling and epigenetic networks mediating the pathogenesis of diabetic complications and metabolic memory. Diabetes and its consequent metabolic disorders can upregulate several growth factors and lipids that can act via their receptors and other mechanisms to trigger multiple signalling pathways, transcription factors (TFs) and crosstalk with epigenetic networks. These events can lead to chromatin remodelling and changes in the transcriptional regulation of key pathological genes in cells from target tissues relevant to various complications of diabetes. Persistence of such epigenetic aberrations (including histone PTMs, DNAme and ncRNAs) may lead to metabolic memory, which is implicated in an increased risk for developing diabetic complications even after normalisation of hyperglycaemia. AT1R, Ang II type 1 receptor; MI, myocardial infarction; oxLDL, Oxidized-LDL; RAGE, Receptor for AGEs; SR, scavenger receptors; TBR, TGF-β receptor

Fig. 2

Chromatin structure and transcription regulation. Chromatin is made up of nucleosome subunits, each of which consists of an octamer of histones wrapped by chromosomal DNA. Lysine residues in the amino-terminal tails of nucleosomal histones are susceptible to several PTMs, including KAc and Kme, which regulate chromatin accessibility to transcription factors (TFs) and RNA polymerase II (labelled in the figure as RNA polymerase). Heterochromatin is marked by repressive histone PTMs, and increased DNAme at promoter CpG islands, leading to chromatin condensation and transcription repression. In contrast, euchromatin is enriched with permissive histone PTMs (H3/H4Kac and H3K4me1-3), and reduced promoter DNAme, leading to open chromatin and increased transcription. In addition, enhancers, which regulate promoters up to several thousand base pairs away, are marked by H3K4me1. Active enhancers are enriched with H3K27ac and the co-activator histone acetyl transferase p300. Actively transcribed gene bodies are enriched with H3K36me3/H3K79me3, whereas H3K27me3 is associated with reduced transcription. In addition, lncRNAs and miRNAs can also regulate gene expression by various post-transcriptional and epigenetic mechanisms (not shown here). TBS, TF binding site; TSS, transcription start site

Fig. 3

Epigenetic mechanisms in Diabetic nephropathy Signal transduction events downstream of high glucose (HG), AGEs and growth factors (TGF-β and Ang II) alter the expression/recruitment of epigenetic factors that mediate or remove histone PTMs and DNA methylation leading to chromatin remodelling. This alters promoter/enhancer access to transcription factors (TFs) such as Smads, SP1 and NF-κB, which are involved in the expression of genes mediating the pathogenesis of diabetic nephropathy. Recent studies also reveal regulatory roles for several miRNAs in diabetic nephropathy, including those that promote fibrotic gene expression in renal cells by targeting transcription repressors (Zeb1/2). Certain lncRNAs have also been shown to modulate fibrotic genes. Inhibitors of TGF-β, Ang II type 1 receptor signalling or miRNAs can block some but not all the events involved in the pathogenesis of diabetic nephropathy, suggesting the need for novel combination therapeutic approaches. Coll1α2, collagen, type I, α2; RAGE, receptor for AGEs

Fig. 4

Epigenetic mechanisms of gene regulation in vascular inflammatory complications, atherosclerosis, retinopathy and metabolic memory. Schematic diagram showing the role of multiple epigenetic mechanisms, including those mediated by miRNAs and lncRNAs, associated with the regulation of genes involved in vascular inflammatory complications. These epigenetic mechanisms increase the expression of NF-κB-regulated inflammatory genes and inhibit the expression of protective anti-oxidant genes, leading to the development of vascular complications such as atherosclerosis and diabetic retinopathy. Studies on in vitro and in vivo models of diabetic complications suggest that persistence of variations in epigenetic histone PTMs and chromatin states at key pathological genes, as well as ncRNA expression, long after the removal from diabetic stimuli play key roles in metabolic memory implicated in an increased risk for diabetic complications. LSD1, lysine-specific demethylase 1; MCP-1, monocyte chemoattractant protein-1; MMP9, matrix metalloproteinase 9