Epigenetic deregulation has a role in the etiology of type 2 diabetes mellitus (T2DM), as well as in the development of its complications. Recent studies show that hyperglycemia can induce both global and site-specific demethylation but the underlying molecular mechanisms are under investigation. Our previous research suggests a role of
PARP-1 (poly-ADP-ribose polymerase) in controlling both the expression and the catalytic activity of Ten-eleven Translocation (TET) enzymes, which are responsible for catalyzing DNA demethylation by converting 5 methyl-cytosine (5mC) into cytosine, through different oxidized intermediates, namely 5hmC, 5fC and 5caC (5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine).
Our preliminary data reveal variation both in DNA methylation state and in cellular PARP activity in PBMCs (peripheral blood mononuclear cells) from a cohort of T2DM patients. In particular, PBMCs from patients with high glycated hemoglobin (HbA1c>7.5%) accumulated the oxidized forms of methylated cytosines (5hmC and 5fC) versus patients with low HbA1c and healthy subjects. In parallel, we observed a significant gain in PAR (polyADP-ribose) level, suggesting that PARP1 activation, most likely induced by the oxidative stress, may cause the block of the DNA demethylation cascade.
This evidence opens up to the hypothesis that PARylation may have implications on the TET enzyme machinery and DNA demethylation. In the present project, we aim to test the hypothesis that the altered DNA methylation pattern, observed in patients with poor glycemic control (HbA1c>7.5%), depends on PARP-1 activity. The understanding of the mechanism controlling 5hmC and 5fC accumulation in T2DM is important, since restoring the control of DNA demethylation cycle promises beneficial effects. In this context, the use of PARP inhibitors may be therapeutically relevant.
