Evaluating the Role of Epigenetic Histone Modifications in the Metabolic Memory of Type 1 Diabetes

  1. the DCCT/EDIC Research Group
  1. 1Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
  2. 2School of Medicine, Case Western Reserve University, Cleveland, OH
  3. 3Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  4. 4Department of Molecular and Cellular Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
  5. 5Department of Biostatistics, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA
  6. 6The Biostatistics Center, George Washington University, Washington, DC
  7. 7Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA
  8. 8Department of Medicine, University of California, San Diego, La Jolla, CA
  1. Corresponding author: Rama Natarajan, rnatarajan{at}coh.org.
  1. F.M., Z.C., and S.G. contributed equally to this study.

Abstract

We assessed whether epigenetic histone posttranslational 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 H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.

Footnotes

  • Received August 14, 2013.
  • Accepted January 11, 2014.

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  1. Diabetes vol. 63 no. 5 1748-1762
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