Evaluating the Role of Epigenetic histone modifications in the Metabolic Memory of Type 1 Diabetes.

  1. the DCCT/EDIC Research Group
  1. 1Departments of Diabetes and Metabolic Diseases Research,
  2. 5Molecular and Cellular Biology and
  3. 6Biostatistics, Beckman Research Institute of City of Hope, Duarte, CA.,
  4. 2Case Western Reserve University, Cleveland, OH,
  5. 3The Hospital for Sick Children, Toronto, Canada,
  6. 4The Biostatistics Center, The George Washington University,
  7. 7University of Massachusetts School of Medicine, Worcester, MA,
  8. 8University of California, San Diego, CA.
  1. Correspondence to: Rama Natarajan, Email: RNatarajan{at}coh.org

Abstract

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.

Footnotes

  • * These authors contributed equally

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

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