Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes

Abstract

The development of the endocrine pancreas is controlled by a hierarchical network of transcriptional regulators. It is increasingly evident that this requires a tightly interconnected epigenetic "programme" to drive endocrine cell differentiation and maintain islet function. Epigenetic regulators such as DNA and histone-modifying enzymes are now known to contribute to determination of pancreatic cell lineage, maintenance of cellular differentiation states, and normal functioning of adult pancreatic endocrine cells. Persistent effects of an early suboptimal environment, known to increase risk of type 2 diabetes in later life, can alter the epigenetic control of transcriptional master regulators, such as Hnf4a and Pdx1. Recent genome-wide analyses also suggest that an altered epigenetic landscape is associated with the β cell failure observed in type 2 diabetes and aging. At the cellular level, epigenetic mechanisms may provide a mechanistic link between energy metabolism and stable patterns of gene expression. Key energy metabolites influence the activity of epigenetic regulators, which in turn alter transcription to maintain cellular homeostasis. The challenge is now to understand the detailed molecular mechanisms that underlie these diverse roles of epigenetics, and the extent to which they contribute to the pathogenesis of type 2 diabetes. In-depth understanding of the developmental and environmental epigenetic programming of the endocrine pancreas has the potential to lead to novel therapeutic approaches in diabetes.

Fig. 1

The role of epigenetic mechanisms in cell lineage determination and maintenance of differentiated states of the endocrine pancreas. The diagram depicts the main steps in pancreas development and the role of several specific epigenetic regulators in these transitions (red arrows see text for details). ES embryonic stem cells

Fig. 2

Potential molecular mechanisms for environmentally induced epigenetic states (adapted from [–136]; see also text for details). For all panels, the environmental factors (diet, drugs, etc.) are labeled in red. a Alterations of the one-carbon metabolism. SHMT serine hydroxymethyl-transferase, MTHFR methylene-tetrahydrofolate reductase, MTR 5-methyl-tetrahydrofolate-homocysteine methyltransferase, BHMT betaine-homocysteine methyltransferase, SAHH S-adenosyl-homocysteine hydrolase, MAT methionine-adenosyl methyltransferase, DHF dihydrofolate, THF tetrahydrofolate, SAM S-adenosyl-methionine, SAH S-adenosyl-homocysteine, ATP adenosine-5′-triphosphate, DNMTs DNA methyltransferases, HMTs histone methyltransferases, Me methylation. b Alterations of the histone deacetylase SIRT1 (sirtuin 1) and histone acetyltransferase (HAT) activities induced by factors that change the intracellular NAD⁺/NADH and Acetyl-CoA/CoA ratios: a high NAD⁺/NADH ratio enhances SIRT1 activity, with consequent histone deacetylation, while high levels of acetyl-CoA (Ac-CoA) stimulate HAT activity, leading to histone acetylation (Ac). c Epigenetic alterations induced in response to nutrient changes via the hexosamine biosynthetic pathway and O-GlcNAcylation of histones and histone modifiers. UDP-GlcNAc uridine diphosphate N-acetylglucosamine, OGT O-GlcNAc transferase, OGA O-GlcNAcase, G -O-GlcNAcylation, PCR2 PcG complex 2, TrxG Trithorax group proteins, Me methylation. d Epigenetic alterations induced by increased oxidative stress. MBD methyl binding proteins (such as MeCP2 and Mbd3), 5mC 5-methylcytosine, 5hmC 5-hydroxymethylcytosine, αKG α-ketoglutarate, FAD flavin adenine dinucleotide, TET ten-eleven translocation (a DNA demethylase), JmjC Jumonji domain-containing (histone demethylases), LSD1 lysergic acid diethylamide (histone demethylase), Pol II polymerase II