The Role of Epigenetics in Type 1 Diabetes

Abstract

Purpose of review: Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence. By implication, such epigenetic changes are non-genetically determined, although they can be affected by inherited genetic variation. Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors. Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut. Further, it remains unclear how they interact to cause the destructive autoimmune process. This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways.

Recent findings: Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response. Specifically, there is evidence of cell type-specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements. Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process.

Keywords: Diabetes; Epigenetics; Methylation; Type 1.

Fig. 1

Interaction between genes, environment and epigenetics in disease. The genome can give rise to many phenotypes. Although genetics, epigenetics and the environment can affect phenotype outcomes independently, it is the complex interaction that gives rise to diseases such as T1D. Evidence for this includes MZ twin studies in which disease concordance was not 100%. Factors such as age and dietary nutrients have been shown to affect the epigenome and some of these epigenetic changes can occur in utero

Fig. 2

DNA methylation and gene expression. A simplified schematic of DNA methylation and its effect on gene expression. DNA methylation occurs by the covalent addition of a methyl group to the 5′ carbon of a cytosine nucleotide. Methylated CpG sites (filled lollipop) are associated with gene silencing, whereas unmethylated sites (unfilled lollipop) are associated with transcriptional activity. In the case of hydroxymethylation, at the 5′ carbon position, the hydrogen molecule is replaced by a hydroxymethyl group

Fig. 3

Chromatin structure with histone modifications. Simplified schematic of the chromatin structure with histone modifications. Different modifications result in conformational changes to the chromatin. The nucleosome is made up of two copies of each histones H2A, H2B, H3 and H4, wrapped by 146 base pairs of DNA. Methylation of H3 on lysine at position 4, 36 and 79 leads to an actively transcribed open chromatin structure. Methylation at H3 on lysine at positions 9 and 27 leads to transcriptional repression. P phosphorylation, Ac acetylation, Me methylation