Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study

Abstract

Epigenetics regulates gene expression and has been confirmed to play a critical role in a variety of metabolic diseases, such as diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), osteoporosis, gout, hyperthyroidism, hypothyroidism and others. The term 'epigenetics' was firstly proposed in 1942 and with the development of technologies, the exploration of epigenetics has made great progresses. There are four main epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodelling, and noncoding RNA (ncRNA), which exert different effects on metabolic diseases. Genetic and non-genetic factors, including ageing, diet, and exercise, interact with epigenetics and jointly affect the formation of a phenotype. Understanding epigenetics could be applied to diagnosing and treating metabolic diseases in the clinic, including epigenetic biomarkers, epigenetic drugs, and epigenetic editing. In this review, we introduce the brief history of epigenetics as well as the milestone events since the proposal of the term 'epigenetics'. Moreover, we summarise the research methods of epigenetics and introduce four main general mechanisms of epigenetic modulation. Furthermore, we summarise epigenetic mechanisms in metabolic diseases and introduce the interaction between epigenetics and genetic or non-genetic factors. Finally, we introduce the clinical trials and applications of epigenetics in metabolic diseases.

Fig. 1

The milestone events related to epigenetics. Key discoveries are highlighted

Fig. 2

Four different epigenetic regulatory mechanisms. The figure presented DNA methylation, histone modification, chromatin remodelling, and ncRNAs. DNA methylation is a universal chemical modification by which methyl groups (Me) are added to the DNA molecule, usually happening on the CpG islands. Histone undergoes several different post-translational modifications, including acetyl (Ac), Me, phosphate (P) and ubiquitin (Ub). Chromatin remodelling complexes change the packaging state of chromatin by moving, sliding, disrupting, or restructuring the nucleosome. ncRNAs are participated in multiple physiological and pathological process by targeting different molecules. This figure was generated with Servier Medical Art (https://smart.servier.com/)

Fig. 3

The roles of epigenetic regulation in metabolic diseases. The figure presented four main metabolic diseases where epigenetic regulation is involved, including diabetes and its complications, obesity, NAFLD and osteoporosis. This figure was generated with Servier Medical Art (https://smart.servier.com/)

Fig. 4

The different influence of DNA methylation in five human tissues for patients with T2D. The figure presented different influence of DNA methylation in patients with T2D in pancreatic islets, adipose tissue, skeletal muscle, liver and blood. This figure was generated with Servier Medical Art (https://smart.servier.com/)

Fig. 5

The interactions between nongenetic risk factors, genetics, and epigenetics in metabolic diseases. Both nongenetic risk factors and genetics could affect epigenetics leading to the development of metabolic diseases. This figure was generated with Servier Medical Art (https://smart.servier.com/)

Fig. 6

Therapeutic application of epigenetics. The figure presented epigenetics-related targets and drugs. This figure was generated with Servier Medical Art (https://smart.servier.com/)