Off the beaten path: DNA methylation and T1D (part 1)
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 disorders with complex heritability like autism spectrum disorder and T1D, both before and after diagnosis.
A recent paper showed DNA methylation preceding T1D diagnosis and clinical onset, after following 87 patients enrolled in the prospective Diabetes Autoimmunity Study in the Young (DAISY) cohort and their frequency-matched controls. DAISY follows children who have a high risk of developing T1D and islet autoimmunity.
- 28 regions were identified as differentially methylated, with 14 being hypermethylated and 14 being hypomethylated. All regions had a consistent direction of methylation compared to controls.
- The majority of these were located near protein-coding regions, with the other 9 regions located near non-coding regions (such as microRNAs or lincRNAs).
- These regions were most commonly found on chromosomes 2 (4 regions), 8 (4 regions) and 17 (4 regions).
- All four of the regions on chromosome 8 were related to DLGAP2, which is related to neuronal glutamate signaling.
- The most significant region was related to the gene LHX6. LHX6 encodes a transcription factor involved in cell fate regulation during embryogenesis.
- With autoantibodies being present in early childhood, researchers thought that intrauterine or prenatal environments may contribute toT1D disease development.
- 26 regions were found to have the same direction of methylation in cord blood.
- Four regions were found to have slight hypomethylation in cord blood, compared to hypermethylation at later time points.
- The region with the largest difference in cord blood was consistently hypermethylated in all analyses, and found near HOPX. HOPX encodes a homeobox transcription cofactor involved in cellular differentiation, proliferation, and T cell function.
- Differential methylation patterns were found in some paternally imprinted genes, with rates of methylation changing over time.
- None of the candidates with differential methylation in this study have been identified in previous twin T1D methylation studies, suggesting various contributions of epigenetic factors throughout disease progression.
Another recent paper studied patient populations involved in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial to better understand how changes in DNA methylation were related to HbA1c-associated complications in T1D. Intensive therapies were found to better prevent microvascular complications and T1D disease progression in DCCT. After an 18-year follow up during EDIC, participants assigned to intensive therapies were found to have lower rates of retinopathy, neuropathy and kidney disease, despite having no differences in HbA1c levels. This may indicate that hyperglycemia may persist after glucose levels are normalized and that epigenetics may play a role.
- Comparing the case group (32 patients from the intensive therapy group with high HbA1c and kidney disease or retinopathy) and the control group (31 patients from the intensive therapy group with low HbA1c and no complications) showed that methylation differences persisted after 17 years. It was not studied if there is a role of methylation in the association between HbA1c and complications.
- 43 locations were found to be associated with HbA1c, with 23 being positively associated and 20 being negatively associated.
- The most significantly associated locations were related to gene TXNIP, a ubiquitously expressed protein that can induce oxidative stress and apoptosis, is highly induced by hyperglycemia and is associated with islet dysfunction.
- Other locations were connected to genes related to diabetes, chromatin function, transcriptional activation or repression, metabolism, inflammation and ribosome biogenesis.
- The effect size of the relation was associated with higher HbA1c levels, suggesting that some changes to methylation are triggered at higher levels that are maintained for longer periods of time.
Part 2 of this series focuses on three papers discussing some of the methylated genes commonly implicated in T1D studies in patients and mouse models.
The takeaway: Methylation may play a role in T1D disease progression and complications and could serve as an early biomarker for the disease, as seen from these longitudinal studies. However, methylated genes are not consistently recognized and implicated across patient populations and research studies. More research across larger populations of T1D patients would need to be done to explore what genes or pathways are consistently implicated.
- Mordaunt, C. E., Jianu, J. M., Laufer, B. I., Zhu, Y., Hwang, H., Dunaway, K. W., . . . Lasalle, J. M. (2020). Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes. Genome Medicine, 12(1).
- Johnson, R. K., Vanderlinden, L. A., Dong, F., Carry, P. M., Seifert, J., Waugh, K., . . . Norris, J. M. (2020). Longitudinal DNA methylation differences precede type 1 diabetes. Scientific Reports, 10(1).
- Chen, Z., Miao, F., Braffett, B. H., Lachin, J. M., Zhang, L., Wu, X., . . . Natarajan, R. (2020). DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes. Nature Metabolism, 2(8), 744-762.