Dataset Information

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?ConclusionsHyperglycemia 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.

SUBMITTER: Yuan EF

PROVIDER: S-EPMC6466651 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Yuan Er-Feng EF Yang Ying Y Cheng Lin L Deng Xujing X Chen Shao-Min SM Zhou Xin X Liu Song-Mei SM

Clinical epigenetics 20190415 1

<h4>Background</h4>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.<h4>Results</h4>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 ...[more]

PMID: 30987683

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Project description:Diffuse intrinsic pontine glioma (DIPG) is a malignant pediatric brain tumor associated with dismal outcome. Recent high-throughput molecular studies have shown a high frequency of mutations in histone-encoding genes (H3F3A and HIST1B) and distinctive epigenetic alterations in these tumors. Epigenetic alterations described in DIPG include global DNA hypomethylation. In addition to the generally repressive methylcytosine DNA alteration, 5-hydroxymethylation of cytosine (5hmC) is recognized as an epigenetic mark associated with active chromatin. We hypothesized that in addition to alterations in DNA methylation, that there would be changes in 5hmC. To test this hypothesis, we performed immunohistochemical studies to compare epigenetic alterations in DIPG to extrapontine adult and pediatric glioblastoma (GBM) and normal brain. A total of 124 tumors were scored for histone 3 lysine 27 trimethylation (H3K27me3) and histone 3 lysine 9 trimethylation (H3K9me3) and 104 for 5hmC and 5-methylcytosine (5mC). An H-score was derived by multiplying intensity (0-2) by percentage of positive tumor nuclei (0-100%).We identified decreased H3K27me3 in the DIPG cohort compared to pediatric GBM (p?<?0.01), adult GBM (p?<?0.0001) and normal brain (p?<?0.0001). H3K9me3 was not significantly different between tumor types. Global DNA methylation as measured by 5mC levels were significantly lower in DIPG compared to pediatric GBM (p?<?0.001), adult GBM (p?<?0.01), and normal brain (p?<?0.01). Conversely, 5hmC levels were significantly higher in DIPG compared to pediatric GBM (p?<?0.0001) and adult GBM (p?<?0.0001). Additionally, in an independent set of DIPG tumor samples, TET1 and TET3 mRNAs were found to be overexpressed relative to matched normal brain.Our findings extend the immunohistochemical study of epigenetic alterations in archival tissue to DIPG specimens. Low H3K27me3, decreased 5mC and increased 5hmC are characteristic of DIPG in comparison with extrapontine GBM. In DIPG, the relative imbalance of 5mC compared to 5hmC may represent an opportunity for therapeutic intervention.

Dataset Information

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

Background

Results

Publications

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

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