Epigenetic 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(ADPribosyl)ation (PARylation) process, a posttranslational modification of proteins catalysed by the poly(ADPribose) 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 casecontrol study were to investigate the association between PARylation and global and sitespecific DNA methylation in T2DM, and to evaluate metabolic correlates. Data were collected from 61 subjects affected by T2DM and 48 healthy individuals. Global levels of poly(ADPribose) (PAR, a surrogate of PARP activity), cytosine methylation (5methylcytosine, 5mC) and of the demethylation intermediates 5hydroxymethylcytosine (5hmC) and 5formylcytosine (5fC) were determined in peripheral blood cells. T2DM subjects presented higher PAR levels than controlsI. Moreover, in T2DM individuals, increased PAR levels were significantly associated with higher HbA1c levels and with the accumulation of the demethylation intermediates 5hmC and 5fC in the genome. Further, we analysed sitespecific DNA methylation profiling of SOCS3, SREBF1 and TXNIP candidate genes. T2DM patients with higher PAR levels showed reduced methylation with increased 5hmC and 5fC levels in specific SOCS3 sites, upregulated SOCS3 expression compared to both T2MD subjects with low PAR levels and controls. This 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 demethylation cascade and may be at the basis of the differential gene expression observed in presence of diabetes.

Increased PARylation impacts the DNA methylation process in type 2 diabetes mellitus / Zampieri, M.; Bacalini, M. G.; Barchetta, I.; Scalea, S.; Bertoccini, L.; Cimini, F. A.; De Matteis, G.; Tagliatesta, S.; Zardo, G.; Cavallo, M. G.; Reale, A.. - (2021), pp. 36-36. ((Intervento presentato al convegno FEBS PARP2021 ADVANCED COURSE PARP: Research on the family of poly(ADP-ribose) polymerases tenutosi a Barcelona, Spain.

Increased PARylation impacts the DNA methylation process in type 2 diabetes mellitus

M. Zampieri;I. Barchetta;L. Bertoccini;F. A. Cimini;S. Tagliatesta;G. Zardo;M. G. Cavallo;A. Reale
2021

Abstract

Epigenetic 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(ADPribosyl)ation (PARylation) process, a posttranslational modification of proteins catalysed by the poly(ADPribose) 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 casecontrol study were to investigate the association between PARylation and global and sitespecific DNA methylation in T2DM, and to evaluate metabolic correlates. Data were collected from 61 subjects affected by T2DM and 48 healthy individuals. Global levels of poly(ADPribose) (PAR, a surrogate of PARP activity), cytosine methylation (5methylcytosine, 5mC) and of the demethylation intermediates 5hydroxymethylcytosine (5hmC) and 5formylcytosine (5fC) were determined in peripheral blood cells. T2DM subjects presented higher PAR levels than controlsI. Moreover, in T2DM individuals, increased PAR levels were significantly associated with higher HbA1c levels and with the accumulation of the demethylation intermediates 5hmC and 5fC in the genome. Further, we analysed sitespecific DNA methylation profiling of SOCS3, SREBF1 and TXNIP candidate genes. T2DM patients with higher PAR levels showed reduced methylation with increased 5hmC and 5fC levels in specific SOCS3 sites, upregulated SOCS3 expression compared to both T2MD subjects with low PAR levels and controls. This 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 demethylation cascade and may be at the basis of the differential gene expression observed in presence of diabetes.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1573414
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