Epigenetic Studies Point to DNA Replication/Repair Genes as a Basis for the Heritable Nature of Long Term Complications in Diabetes

J Diabetes Res. 2016;2016:2860780. doi: 10.1155/2016/2860780. Epub 2016 Feb 14.


Metabolic memory (MM) is defined as the persistence of diabetic (DM) complications even after glycemic control is pharmacologically achieved. Using a zebrafish diabetic model that induces a MM state, we previously reported that, in this model, tissue dysfunction was of a heritable nature based on cell proliferation studies in limb tissue and this correlated with epigenetic DNA methylation changes that paralleled alterations in gene expression. In the current study, control, DM, and MM excised fin tissues were further analyzed by MeDIP sequencing and microarray techniques. Bioinformatics analysis of the data found that genes of the DNA replication/DNA metabolism process group (with upregulation of the apex1, mcm2, mcm4, orc3, lig1, and dnmt1 genes) were altered in the DM state and these molecular changes continued into MM. Interestingly, DNA methylation changes could be found as far as 6-13 kb upstream of the transcription start site for these genes suggesting potential higher levels of epigenetic control. In conclusion, DNA methylation changes in members of the DNA replication/repair process group best explain the heritable nature of cell proliferation impairment found in the zebrafish DM/MM model. These results are consistent with human diabetic epigenetic studies and provide one explanation for the persistence of long term tissue complications as seen in diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Fins / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Computational Biology
  • DNA Methylation
  • DNA Repair / genetics*
  • DNA Repair Enzymes / genetics*
  • DNA Replication / genetics*
  • Diabetes Complications / genetics*
  • Diabetes Complications / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications*
  • Disease Models, Animal
  • Energy Metabolism / genetics*
  • Epigenesis, Genetic*
  • Gene Expression Profiling / methods
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease
  • Heredity*
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Zebrafish


  • Blood Glucose
  • DNA Repair Enzymes