Epigenetics and diabetes treatment: an unrealized promise?
Panel 1. Epigenomic modifications. The acetylation and methylation state of histones can impact whether the DNA is bound in a closed, “repressive” state or an open, “active” state. Transitions between the two states occur with the help of histone acetyltransferase (HAT) or histone deacetylase (HDAC) enzymes. Epigenetic signatures are critical to proper beta cell differentiation and development. [magnify ]
There are several main types of modifications that contribute to the epigenome (figure 1). The first type of modification is DNA methylation. Methylation typically occurs at the 5-position of cytosine to generate 5-methyl cytosine. This type of DNA methylation is frequently associated with gene silencing and decreased gene expression via one of two mechanisms: 1) enhanced promoter binding by transcriptional repressors or 2) inhibition of binding by other DNA-binding proteins. DNA methylation is decreased, across the organism, during development. The second group of modifications, histone modifications, includes lysine acetylation, lysine/arginine methylation, serine/threonine phosphorylation, and lysine ubiquitination/sumoylation. Two marks in particular, trimethylation of the fourth lysine on histone 3 (H3K4me3) and trimethylation of the 27th lysine on histone 3 (H3K27me3), have been studied extensively for their roles in transcription and disease progression. H3K4me3 is typically seen as an “activating” mark at promoters while H3K27me3 has been correlated with transcriptional repression. Furthermore, during development, one of these marks is removed to allow repression or activation of corresponding genes.
The epigenome is heavily impacted by environmental factors, particularly during embryogenesis and early development. To illustrate, studies have shown that intrauterine malnutrition is a risk factor for developing T2DM in adulthood. In animals, it has been shown that intrauterine growth retardation (IUGR) leads to decreased expression of Pdx1, a transcription factor which is essential to proper beta cell development, reduced beta cell mass, and subsequent T2DM. Further experiments using ChIP, demonstrated that decreased Pdx1 expression could be correlated with lower levels of activating epigenomic marks, including histone H3 and H4 acetylation at the Pdx1 locus and lower levels of H3K4me3 marks in the Pdx1 promoter. These data suggest that epigenetic profiling could be used to define biomarkers for early disease detection or to assess disease risk factors.
Epigenetic profiling may also have a role to play in the treatment of diabetes. One of the major challenges in the treatment of diabetes is the development of an in vitro protocol for directed differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) into mature beta cells. Current in vitro protocols for directed differentiation do not account for epigenetic signals and often yield polyhormonal cells that are not glucose-responsive. The authors propose that enzymes which regulate epigenetic modifications such as, histone acetyltransferases (HATs) and histone deacetylases (HDACs), may be relevant targets for diabetes therapies as evidenced by studies showing that treatment of pancreatic explants with the HDAC class IIa inhibitor, MC1568, promotes an increase in beta and delta cells.
Taken as a whole, the authors of this review offer a number of compelling reasons why further study of the epigenome is necessary for developing successful protocols for directed differentiation of ESCs. Additional studies regarding epigenetic regulatory enzymes (HATs and HDACs), should also be pursued as possible therapeutic targets.