Parp inhibition prevents ten eleven translocase enzyme activation and hyperglycemia induced DNA demethylation

  1. Robert V. Intine1,2
  1. 1Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL
  2. 2Dept of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL
  1. Corresponding Author: Robert V. Intine, E-mail: robert.intine{at}rosalindfranklin.edu

Abstract

Studies from human cells, rats and zebrafish have documented that hyperglycemia induces the demethylation of specific cytosines throughout the genome. Previously, we documented that a subset of these changes become permanent and may provide in part a mechanism for the persistence of complications referred to as the metabolic memory phenomenon. In this report we present studies aimed at elucidating the molecular machinery that is responsible for the hyperglycemia induced DNA demethylation observed. To this end, RNA expression and enzymatic activity assays indicate that the ten-eleven translocation family of enzymes (Tet) were activated by hyperglycemia. Furthermore through the detection of intermediates generated via conversion of 5mC back to the unmethylated form the data were consistent with the use of the Tet-dependent iterative oxidation pathway. In addition, evidence is provided that the Poly-ADP ribose polymerase enzyme’s (Parp) activity is required for activation of Tet activity as the use of a Parp inhibitor prevented demethylation of specific loci and the accumulation of Tet induced intermediates. Remarkably, this inhibition was accompanied by a complete restoration of the tissue regeneration deficit that is also induced by hyperglycemia. The ultimate goal of this work is to provide potential new avenues for therapeutic discovery.

  • Received December 19, 2013.
  • Accepted April 1, 2014.

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