DNA methylation and its role in the pathogenesis of diabetes

Abstract

Although the factors responsible for the recent increase in the prevalence of diabetes worldwide are not entirely known, the morbidity associated with this disease results in substantial health and economic burden on society. Epigenetic modifications, including DNA methylation have been identified as one mechanism by which the environment interacts with the genome and there is evidence that alterations in DNA methylation may contribute to the increased prevalence of both type 1 and type 2 diabetes. This review provides a summary of DNA methylation and its role in gene regulation, and includes descriptions of various techniques to measure site-specific and genome-wide DNA methylation changes. In addition, we review current literature highlighting the complex relationship between DNA methylation, gene expression, and the development of diabetes and related complications. In studies where both DNA methylation and gene expression changes were reported, DNA methylation status had a strong inverse correlation with gene expression, suggesting that this interaction may be a potential future therapeutic target. We highlight the emerging use of genome-wide DNA methylation profiles as a biomarker to predict patients at risk of developing diabetes or specific complications of diabetes. The development of a predictive model that incorporates both genetic sequencing and DNA methylation data may be an effective diagnostic approach for all types of diabetes and could lead to additional innovative therapies.

Keywords: DNA methylation; epigenetics; insulin secretion; insulin sensitivity; islets; type 2 diabetes.

Figure 1

A) CpGs at gene promoter sites: methylated and unmethylated. B) Heterochromatin protein 1 (HP1) binds to the trimethylated histone H3 at lysine 9 (H3K9me3), and then recruits DNA methyltransferase (DNMT). DNMTs in turn increase DNA methylation resulting in a compact chromatin and transcription silencing. Whereas, increased histone acetyl transferase activity, increased histone H3 (H3) and histone 4 (H4) acetylation (Ac), and increased trimethylation of histone H3 at lysine 4 (H3K4me3) prevents DNA methylation leading to a relaxed/open chromatin and transcription activation.

Figure 1

A) CpGs at gene promoter sites: methylated and unmethylated. B) Heterochromatin protein 1 (HP1) binds to the trimethylated histone H3 at lysine 9 (H3K9me3), and then recruits DNA methyltransferase (DNMT). DNMTs in turn increase DNA methylation resulting in a compact chromatin and transcription silencing. Whereas, increased histone acetyl transferase activity, increased histone H3 (H3) and histone 4 (H4) acetylation (Ac), and increased trimethylation of histone H3 at lysine 4 (H3K4me3) prevents DNA methylation leading to a relaxed/open chromatin and transcription activation.

Figure 2

De novo DNA methyltransferases and maintenance DNA methyltransferases.

Figure 3

DNA methylation and its relationship to Type 1 and Type 2 diabetes. There is a complex interaction between genetics, epigenetics and environment (shown by dashed arrows). Epigenetics (DNA methylation) in combination with genetic and environmental stimuli could either impair pancreatic development and insulin secretion, or lead to insulin resistance at peripheral tissues such as liver, muscle and adipose. A combination of impaired insulin secretion and insulin resistance underlie Type 2 diabetes, whereas impaired pancreatic development and insulin secretion underlie Type 1 diabetes. Genetic inheritance (purple arrows) or abnormal environmental stimuli (blue arrows) alone could either impair pancreatic function, or lead to insulin resistance independently.