Epigenetic control of β-cell function and failure

Abstract

Type 2 diabetes is a highly heritable disease, but only ∼15% of this heritability can be explained by known genetic variant loci. In fact, body mass index is more predictive of diabetes than any of the common risk alleles identified by genome-wide association studies. This discrepancy may be explained by epigenetic inheritance, whereby changes in gene regulation can be passed along to offspring. Epigenetic changes throughout an organism's lifetime, based on environmental factors such as chemical exposures, diet, physical activity, and age, can also affect gene expression and susceptibility to diabetes. Recently, novel genome-wide assays of epigenetic marks have resulted in a greater understanding of how genetics, epigenetics, and the environment interact in the development and inheritance of diabetes.

Keywords: Diabetes; Epigenetics; Methylome; β-cell.

Figure 1. Obesity contributes to Type 2 Diabetes

A higher BMI correlates with a higher incidence of diabetes. Reprint from [7].

Figure 2. Models of demethylation mediated by the TET enzymes

A) TET-assisted active demethylation. The TET enzymes sequentially oxidize methylated cytosines (5mC) into 5-hydroxymethylcytosine, then 5-formylcytosine (5fC) and finally 5-carboxycytosine (5caC). These altered cytosines can then be excised by the thymine DNA glycosylase enzyme (TDG) and replaced with an unmodified cytosine by part of the base-excision repair pathway. B) TET-assisted passive demethylation. The TET enzymes oxidize methylated cytosines into 5hmC, which are a poor substrate for DNMT activity after DNA replication. With each cycle of replication, the methylation status is further diluted.

Figure 3. Using the methylation status of the insulin promoter in blood to assess β-cell death

A–B) The insulin promoter is differentially methylated in β-cell compared to other cell types. The methylation status of the insulin promoter can be detected using bisulfite sequencing. Arrows represent primers used for DNA amplification. (A) depicts the unmethylated insulin promoter in β-cells while (B) depicts the methylated and silenced insulin promoter in all other cells types. C) Massive β-cell death can be detected with bisulfite sequencing with a simple blood test, because in those circumstances, up to 5% of cell-free DNA in the blood comes from β-cells.

Figure 4. Epigenetic inheritance can be multigenerational or transgenerational

A) Multigenerational inheritance refers to a change in a trait or phenotype in the F1 offspring of males or non-pregnant females (F0) exposed to a stimulus that impacts the epigenome without changing the DNA sequence. B) In the case of a pregnant female exposed to an environmental toxin, for instance the F0 parent, the F1 fetus, and the F2 germline within the fetus are all exposed. Therefore, in this case, only if the F3 generation also shows an epigenetically altered phenotype is it considered transgenerational inheritance.