Epigenetic modifications in pancreas development, diabetes, and therapeutics

Abstract

A recent International Diabetes Federation report suggests that more than 463 million people between 20 and 79 years have diabetes. Of the 20 million women affected by hyperglycemia during pregnancy, 84% have gestational diabetes. In addition, more than 1.1 million children or adolescents are affected by type 1 diabetes. Factors contributing to the increase in diabetes prevalence are complex and include contributions from genetic, environmental, and epigenetic factors. However, molecular regulatory mechanisms influencing the progression of an individual towards increased susceptibility to metabolic diseases such as diabetes are not fully understood. Recent studies suggest that the pathogenesis of diabetes involves epigenetic changes, resulting in a persistently dysregulated metabolic phenotype. This review summarizes the role of epigenetic mechanisms, mainly DNA methylation and histone modifications, in the development of the pancreas, their contribution to the development of diabetes, and the potential employment of epigenetic modulators in diabetes treatment.

Keywords: DNA methylation; epigenetic modulators; gestational diabetes; histone modifications; pancreas; type 1 diabetes; type 2 diabetes.

Figure 1

Schematic representation of the role of histone modifications in pancreas development and α and β cell function. On the left panel, the different histone modifiers and the known histone modifications with their effects on progenitor cell fates are indicated with arrows. The right panel shows the different histone modifications that regulate endocrine cell functions, mainly α‐ and β‐cells, which are the key regulators of insulin metabolism and signalling, Figure generated using BioRender. Red colour means the histone mark is removed, whereas green colour means the histone mark is added. Similarly, green arrows show upregulation, and red arrows show downregulation [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Histone modifications in various aspects of pancreatic development and pathogenesis of diabetes. H2A.Z serves as a histone mark, which upregulates gene expression by facilitating chromatin access to the transcription machinery. The monoubiquitination of K199 by PRC1 facilitates chromatin compaction by further recruiting PRC2, which, in turn, catalyzes H3K27Me3, a gene repression mark. H3K27Me, H3K9Me, and H3K36Me serve as histone marks of target gene repression at gene promoters, whereas H3K4Me, H3R2Me, and H3Ac promote target gene activation. All these marks are altered in diabetes. H4R3 methylation by PRMT1 activates target gene expression. H4K8 and H4K16 acetylation's target genes expressions are targets of Class II and Class III HDACs. Target gene boxes with green outlines show gene activation, and the ones with red outlines show gene repression. Figure generated using BioRender [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Gene network analysis of the gene promoters which are differentially methylated in T1D, T2D, and GDM. The arrows indicate the targets. Insulin is shown in the middle, whose expression is altered as a result of the change in the methylation level. Figure generated using String and Cytoscape. GDM, gestational diabetes mellitus [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Pathway enrichment for the genes whose promoters are regulated by DNA methylation in the pancreas. The gene enrichment pathways for T1D, T2D, and GDM were generated using the web tool Enrichr, and the associated pathways were plotted using ggplot2 and R‐package. The picture show how Insulin and the associated signalling pathways are altered in T1D, T2D, and GDM in relation to the pancreas (p value <0.05). GDM, gestational diabetes mellitus [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5

Schematic representation of the role of HDACs and HDAC inhibitors in glucose homeostasis. HDAC I/IIs catalyze the deacetylation of target histones and aid in the compaction of chromatin, which restricts transcription factors access to DNA, resulting in target gene repression. The inhibition of HDAC I/II maintains histone acetylation at the IRS2 promoter and promotes IRS2 expression. HDAC inhibition resulting in FoxO1 acetylation also maintains glucose homeostasis. HDAC III (e.g., SIRT1/SIRT2) activation promotes PDX1 expression through deacetylation of FoxA2, thereby maintaining β‐cell development and insulin secretion. Figure generated using BioRender. Green arrows show upregulation, and red arrows show downregulation. HDAC, histone deacetylase [Color figure can be viewed at wileyonlinelibrary.com]