Parp inhibition prevents ten-eleven translocase enzyme activation and hyperglycemia-induced DNA demethylation.
Studies from human cells, rats, and zebrafish have documented that hyperglycemia (HG) induces the demethylation of specific cytosines throughout the genome. We previously 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 HG-induced DNA demethylation observed. To this end, RNA expression and enzymatic activity assays indicate that the ten-eleven translocation (Tet) family of enzymes are activated by HG. Furthermore, through the detection of intermediates generated via conversion of 5-methyl-cytosine 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 activity of the poly(ADP-ribose) polymerase (Parp) enzyme is required for activation of Tet activity because 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 HG. The ultimate goal of this work is to provide potential new avenues for therapeutic discovery.
Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
Nyembezi
N
Dhliwayo
Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
Michael P
MP
Sarras
Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
Ernest
E
Luczkowski
Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL.
Samantha M
SM
Mason
Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL Department of Cell Biology and Anatomy, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL robert.intine@rosalindfranklin.edu.
Robert V
RV
Intine
D058500:Animal Fins / Q000502:physiology; D000818:Animals; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D049308:Dioxygenases / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006943:Hyperglycemia / Q000503:physiopathology*; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines; D029961:Zebrafish Proteins; C095653:1,5-dihydroxyisoquinoline; D004247:DNA; D049308:Dioxygenases