Epigenetic Changes in Diabetes and Cardiovascular Risk
Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species.
The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression.
Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type–specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease.
http://circres.ahajournals.org/content/118/11/1706/tab-figures-data
Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals.
The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them.
Introduction
Epigenetics can be defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence (1). Epigenomics is the study of genome-wide epigenetic modifications. Epigenetics was introduced as a theoretical framework seeking to understand putative undisclosed relations between genes and environmental settings (diet, inactivity, smoking, etc.) to generate a phenotype (2). Epigenetics can provide some insights to help understand genetic fetal programming, monozygotic twin differences, and chronic disease onset in adults, which interact with dietary intake and nutritional processes.
Some epigenetic information might be inherited from one generation to the next. Although DNA methylation status is currently the most-studied epigenetic marker, there is increasing recognition that other modifications such as those of the histone code can modify the chromatin organization and folding (euchromatin vs. herochromatin) in such a way as to affect gene expression patterns (3).
These mechanisms, together with other transcriptional regulatory events, ultimately regulate gene activity and expression during development and differentiation or in response to nutritional and environmental stimuli.
Important recent investigations have highlighted that chromatin modifications/accessibility mark important disease-relevant regulatory regions in the genome (4–6, 8). Some of these studies suggest that common phenotypically associated single nucleotide polymorphisms (SNPs)7, which are enriched for expression quantitative trait loci, might act by altering gene regulatory regions (4).
Whereas many expression quantitative trait loci and regulatory variants act universally, some of the most relevant to disease might have tissue-specific activity (9). In this sense, chromatin state differences between cell types are related to cell type-specific gene functions (5).
The Encyclopedia of DNA Elements project (6) has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification within different cell types (including up to 12 histone modifications), which are allowing researchers to assign functional attributes to genomic regions.
The study of Ernst et al. (5) also revealed that the levels of DNA methylation usually correlate with chromatin accessibility and that, because most of the disease-associated SNPs are either intronic or intergenic and show consistently higher overlap with Encyclopedia of DNA Elements annotations, it seems like the genome-wide association study-identified regions are the ideal place to look for such epigenetic signatures.
The National Human Genome Research Institute Catalogue of Published genome-wide association study provides a quality-controlled, manually curated, literature-derived collection of all published GWA studies, which, as of 1 October 2013, included 1724 publications and 11,680 SNPs (7).
One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes.
Thus, Maurano et al. (8) demonstrated that disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks in a tissue-specific way.