Evaluating the Role of Epigenetic histone modifications in the Metabolic Memory of Type 1 Diabetes.
We assessed whether epigenetic histone post-translational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3lysine-9 acetylation (H3K9Ac), H3K4-trimethylation (H3K4Me3) and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects [cases, mean DCCT HbA1c >9.1% (76 mmol/mol) and progression of retinopathy or nephropathy by EDIC year 10 of follow-up] versus 30 DCCT intensive treatment subjects [controls, mean DCCT HbA1c <7.3% (56 mmol/mol) and without progression]. Monocytes from cases had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) as compared to controls (p=0.0096). Among the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c during DCCT and EDIC (each p<2.2E-16). Of note, the top 38 case hyperacetylated promoters (p<0.05) included over fifteen genes related to the NF-κB inflammatory pathway, and were enriched in genes related to diabetic complications. These results suggest an association between HbA1c and H3K9Ac and a possible epigenetic explanation for metabolic memory in humans.
* These authors contributed equally
- Received August 14, 2013.
- Accepted January 11, 2014.
- © 2014 by the American Diabetes Association.
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