Hyperglycemia affects global 5-methylcytosine and 5-hydroxymethylcytosine in blood genomic DNA through upregulation of SIRT6 and TETs

Abstract

Background Accumulating evidence suggests that epigenetic changes play key roles in the pathogenesis of type 2 diabetes mellitus (T2DM). However, the dynamic regulation of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in diabetic peripheral blood DNA remains to be elucidated. Results We collected fasting blood samples (104 patients and 108 healthy controls) and glucose-stimulated blood samples at different time points (11 patients and 5 healthy controls underwent oral glucose tolerance test (OGTT)), as well as blood samples from six couples of diabetic and control rats. A HPLC-MS/MS system was used for quantifying global 5mC and 5hmC in genomic DNA from white blood cells (WBCs), and qPCR was performed for detecting mRNA expression of SIRT6 and TETs . We found that global 5mC decreased, while global 5hmC increased in both patients and diabetic rats, with lower 5mC being a risk factor of T2DM (OR = 0.524, 95%CI 0.402–0.683, p = 1.64 × 10 −6 ). The OGTT data from patients showed that 5mC declined within 1 h and then returned to the fasting status at 2 h, while 5hmC rose from 0.5 h to 3 h with increasing glucose. However, the similar patterns were not found in the controls. The mRNA expression of TET2 , TET3 , and SIRT6 was upregulated in patients ( p = 0.012, p = 0.026, and p = 0.035, respectively). The similar results were observed in diabetic OGTT and rats. Correlation analysis indicated that SIRT6 was positively correlated with TET2 in humans ( r = 0.277, p < 0.001) and rats ( r = 0.942, p < 0.001), in addition to a correlation between glucose and SIRT6 ( r = 0.162, p = 0.045) and TET2 ( r = 0.174, p = 0.036). Conclusions Hyperglycemia appeared to promote the mRNA expression of SIRT6 and TETs , which in turn might cause the dynamic changes of 5mC and 5hmC in WBCs from T2DM patients. Electronic supplementary material The online version of this article (10.1186/s13148-019-0660-y) contains supplementary material, which is available to authorized users.

Incretin drugs effect on epigenetic machinery: New potential therapeutic implications in preventing vascular diabetic complications

“…DNA methyltransferases (DNMTs) and DNA demethylases maintain this process with an intricate balance. 5,6 Several studies have been conducted to investigate the association between hyperglycemia, epigenetic modifications and epigenetic mediators. In retinal endothelial cells, high glucose increased DNMT1 mRNA by fourfold in bovines and twofold in humans but, it had no significant effect on DNMT3A and DNMT3B gene transcripts in both "in vitro" and "in vivo" experiments.…”

“…3 Furthermore, a very recent study demonstrated that hyperglycemia affects global 5-methylcytosine (5-mC) and 5-hmC in blood genomic DNA of type 2 diabetic patients through an upregulation of SIRT6 and TETs. 5 Interestingly, incretin-based drugs are promising antihyperglycemic agents used for T2D treatment. In addition to glucose-lowering effects, emerging data show their antiatherogenic effects (including modulation of inflammatory response, reduction of intima-media thickening, improvement in lipid profiles), with the capability to stabilize atherosclerotic plaques and treat arterial inflammation.…”

“…DNA methylation is a dynamic process in which methylation could be synthesized “de novo”, maintained or removed. DNA methyltransferases (DNMTs) and DNA demethylases maintain this process with an intricate balance 5,6 …”

“…Accordingly, people with type 2 diabetes (T2D) or impaired glucose metabolism had DNA hypo‐methylation compared to normoglycemic individuals 3 . Furthermore, a very recent study demonstrated that hyperglycemia affects global 5‐methylcytosine (5‐mC) and 5‐hmC in blood genomic DNA of type 2 diabetic patients through an upregulation of SIRT6 and TETs 5 …”

New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation

“…Significant changes of TET2 expression and 5hmC abundance have been found in the umbilical veins of gestational diabetes mellitus (GDM) pregnancies (Sun et al, 2016) and a recent study reported that hyperglycaemic conditions had an adverse effect on the DNA 5-hydroxymethylome via the destabilization of TET2 (Yuan et al, 2019). In addition, hyperglycaemia appeared to promote the mRNA expression of SIRT6 and TET2, which, in turn, might cause the dynamic changes of 5mC and 5hmC in peripheral white blood cells (PWBCs) from T2DM patients (Yuan et al, 2019). Indeed, the relationship between hyperglycaemia and SIRT6 DNA promoter methylation level has not been investigated yet.…”