Off the beaten path: DNA methylation and T1D (part 2)
By: Shruthi Kandalai
Epigenetic changes refer to changes made to DNA that can alter gene expression without affecting the sequence itself. Epigenetic changes include DNA methylation and chromatin remodeling, with the former being the most often studied. DNA methylation usually involves the addition of a methyl group, decreasing the accessibility of DNA and blocking transcription factors from binding, possibly turning off genes. DNA methylation may be caused by environmental stimuli and influence disease development or may be a consequence of disease progression. Methylation has recently been implicated in T1D, both before and after diagnosis.
Part 1 of this series focuses on two papers studying longitudinal changes to DNA methylation from human trials related to T1D, including Diabetes Autoimmunity Study in the Young (DAISY), Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial.
A research group published a review showing that epigenetic changes in methylation have been implicated in all three of the main forms of diabetes, including T1D.
- A methylation analysis of lymphoblast cell lines for T1D showed 88 sites with significant changes, with clusters related to immune response and defense response pathways. Genes previously associated with T1D (HLA, INS, IL2RB AND CD226) were also implicated.
- Another methylation analysis of whole blood from T1D monozygotic twins showed modest methylation differences for adaptive immune MHC, genes associated with T1D (BACH2, INS, IGF2 AND CLEC16A) and other genes (MAGI2, FANCC AND PCDHB16).
- Recent studies in T1D non-obese diabetic mice have also seen changes in methylation of insulin genes Ins1 and Ins2. These studies have also shown increases in inflammatory cytokines (TNF, IFNγ, IL6 and IL1B), which may induce increased methylation and decreased insulin levels.
Recently, a research group sought to study if the methylation changes to insulin related genes (Ins, Ins1 and Ins2) were also present in T1D patients, as these are important to T1D pathogenesis. Whole blood from 20 Greek children and adults and 20 healthy, non-obese controls was analyzed.
- Increased methylation at multiple positions of the INS gene was found, though only two of these were statistically significant.
- Of the two significantly hypermethylated sites, one is partially supported by previous research in human pancreatic tissue, while the other is in contrast with previous studies.
Another study adds to the data regarding changes to HLA methylation, studying the HLA-DQA1 allele in whole blood of 61 T1D patients and 39 healthy controls.
- Alleles of both HLA-DRB1 and HLA-DQA1 have been found to be related to an increased or decreased risk of T1D, though their effect on T1D is not yet fully understood.
- While some regions were hypermethylated, these were not correlated with HLA-DQA1 allele expression.
- No significant methylation differences of HLA-DQA1 were found between T1D patients and controls.
The takeaway: Methylation may play a role in T1D disease progression. However, methylated genes are not consistently recognized and implicated across patient populations and research studies. This makes it hard to determine which methylation patterns are most important in detecting the disease, and thus more research with larger patient populations needs to be done to explore what genes or pathways are consistently implicated.
- Bansal, A., & Pinney, S. E. (2017). DNA methylation and its role in the pathogenesis of diabetes. Pediatric Diabetes, 18(3), 167-177.
- Mouzaki, K., Kotanidou, E., Fragou, A., Kyrgios, I., Giza, S., Kleisarchaki, A., . . . Galli‑Τsinopoulou, A. (2020). Insulin gene promoter methylation status in Greek children and adolescents with Type 1 Diabetes. Biomedical Reports, 13(4), 31st ser.
- Zajacova, M., Kotrbova-Kozak, A., Silhova, E., & Cerna, M. (2016). DNA methylation and mRNA expression of HLA-DQA1 alleles in type 1 diabetes mellitus. Immunology, 148(2), 150-159.