Abstract
BackgroundEpigenetic modifications, such as DNA methylation, can influence the genetic susceptibility to type 2 diabetes mellitus (T2DM) and the progression of the disease. Our previous studies demonstrated that the regulation of the DNA methylation pattern involves the poly(ADP-ribosyl)ation (PARylation) process, a post-translational modification of proteins catalysed by the poly(ADP-ribose) polymerase (PARP) enzymes. Experimental data showed that the hyperactivation of PARylation is associated with impaired glucose metabolism and the development of T2DM. Aims of this case–control study were to investigate the association between PARylation and global and site-specific DNA methylation in T2DM and to evaluate metabolic correlates.ResultsData were collected from 61 subjects affected by T2DM and 48 healthy individuals, recruited as controls. Global levels of poly(ADP-ribose) (PAR, a surrogate of PARP activity), cytosine methylation (5-methylcytosine, 5mC) and de-methylation intermediates 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC) were determined in peripheral blood cells by ELISA-based methodologies. Site-specific DNA methylation profiling of SOCS3, SREBF1 and TXNIP candidate genes was performed by mass spectrometry-based bisulfite sequencing, methyl-sensitive endonucleases digestion and by DNA immuno-precipitation. T2DM subjects presented higher PAR levels than controls. In T2DM individuals, increased PAR levels were significantly associated with higher HbA1c levels and the accumulation of the de-methylation intermediates 5hmC and 5fC in the genome. In addition, T2DM patients with higher PAR levels showed reduced methylation with increased 5hmC and 5fC levels in specific SOCS3 sites, up-regulated SOCS3 expression compared to both T2DM subjects with low PAR levels and controls.ConclusionsThis study demonstrates the activation of PARylation processes in patients with T2DM, particularly in those with poor glycaemic control. PARylation is linked to dysregulation of DNA methylation pattern via activation of the DNA de-methylation cascade and may be at the basis of the differential gene expression observed in presence of diabetes.
Highlights
Epigenetic modifications, such as DNA methylation, can influence the genetic susceptibility to type 2 diabetes mellitus (T2DM) and the progression of the disease
After stratifying the T2DM population in two subgroups of patients with PAR levels above or below the median PAR value, we found that subjects with high PAR had significantly greater HbA1c levels than those with low PAR (p = 0.004) (Additional file 2: Table S1)
Increased PARylation may interfere with the dynamic balance between methylation and de-methylation, its upregulation may underpin DNA hypomethylation [35,36,37,38,39] and the increase in hydroxymethylation [40, 41] observed in T2DM individuals with poor glycaemic control
Summary
Epigenetic modifications, such as DNA methylation, can influence the genetic susceptibility to type 2 diabetes mellitus (T2DM) and the progression of the disease. Experimental data showed that the hyperactivation of PARylation is associated with impaired glucose metabolism and the development of T2DM Aims of this case–control study were to investigate the association between PARylation and global and site-specific DNA methylation in T2DM and to evaluate metabolic correlates. DNA methylation plays an important role in the development of several diseases, such as T2DM itself [4,5,6,7] This is because of its potential to alter gene expression directly, by inhibiting the binding of specific transcription factors, and indirectly, by recruiting methyl-CpG-binding proteins and their associated repressive chromatin remodelling activities [8]. DNA methylation modifications are reversible yet heritable, conferring important contributions to epigenetic memory
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