Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Haertle, Larissa; Hajj, Nady El; Dittrich, Marcus; Müller, Tobias; Nanda, Indrajit; Lehnen, H; Haaf, Thomas

doi:10.1186/s13148-017-0329-3

Cited by 96 publications

(100 citation statements)

References 62 publications

(71 reference statements)

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“…Consistently, our study is supported by previous studies reporting that HIF3A was involved in adipocyte differentiation, insulin resistance, and glucose metabolism (Haertle et al, ), which are key factors contributing to GDM pathogenesis (Davis, Gunderson, Gunderson, Gyllenhammer, & Goran, ). For example, two CpG methylation sites in intron 1 of HIF3A gene, cg16672562, and cg46801562, have significant correlation with obesity (Lee et al, ).…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, HIF3A expression in subcutaneous adipose tissue was adversely associated with insulin resistance (Main et al, ). In addition, a methylation screening via bisulfite pyrosequencing reported that the average methylation of 11 CpG islands in HIF3A was significantly higher in the blood of GDM patients compared to the controls (Haertle et al, ). Taken together, our data have revealed a role of HIF3A in GDM development, and further study should focus on finding downstream target genes of HIF3A .…”

Section: Discussionmentioning

confidence: 99%

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Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus

Zhang

Chen

et al. 2019

Molec Gen & Gen Med

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Background Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance during pregnancy, and will lead to high risk of diabetes even after pregnancy. Hypoxia‐inducible factor (HIF) family proteins are transcriptional factors that are highly correlated with methylation, which might be involved in the regulation of GDM. Methods Baseline clinical characteristics of the GDM patients and healthy women were analyzed. Omental tissue from GDM patients and control groups were collected and detected for the expression levels of HIF1A, HIF2A, and HIF3A. The CpG islands of HIF3A promoter were predicted by “methprimer” software, and the methylation level of CpG islands was detected by bisulfite sequencing PCR. Results HIF3A was downregulated in the omental tissue from GDM patients, whereas HIF1A and HIF2A were not affected. Furthermore, HIF3A expression was positively correlated with levels of estrogen receptor α (ESR1) and solute carrier family 2 member 4 (SLC2A4). Moreover, CpG islands of HIF3A promoter were highly methylated in GDM patients. In addition, methylation level of CpG islands could be upregulated by Estradiol (E2) treatment, since high dose of E2 reduced HIF3A mRNA expression in 3T3‐L1 adipocytes. Conclusion Our findings demonstrate that the expression level of HIF3A, but not HIF1A or HIF2A, is downregulated in GDM patients. The methylation status of HIF3A promoter region is highly correlated with GDM, which could be a novel therapeutic target for GDM treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus

Zhang

Chen

et al. 2019

Molec Gen & Gen Med

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“…There are, however, robust observational data both supporting and refuting an observational link between 1-CM function-through studies on tHcy, folate, or vitamin B 12 and genetic studies, based on either the MTHFR polymorphism alone (44) or a cassette of genetic markers (45)and aberrant metabolic function (46,47), obesity, or type 2 diabetes (48,49). Results from the current study add further evidence to that literature and motivate future functional work on these identified loci that may allow more robust conclusions to be drawn regarding the role of 1-CM function in the etiology of metabolic disease (41,50,51).…”

Section: Dmps In Hif3a Are Associated With Aspects Of Metabolic Syndromementioning

confidence: 56%

“…HIF3A is thought to act as a transcriptional regulator in adaptive response to low-oxygen tension and has a role in glucose, lipid, and amino acid metabolism as well as adipocyte differentiation (37,38). Interestingly, hypermethylation at the HIF3A locus has previously been positively associated with variability in BMI (39), adipose tissue dysfunction (40), and risk of gestational diabetes mellitus (41). There have also been speculations about the role of genetic variants in the PLEKHH2 region as a potential risk factor for diabetic neuropathy (42).…”

Section: Dmps In Hif3a Are Associated With Aspects Of Metabolic Syndromementioning

confidence: 99%

Interaction between plasma homocysteine and the MTHFR C.677C > T polymorphism is associated with site‐specific changes in DNA methylation in humans

et al. 2018

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One-carbon metabolism provides a direct link among dietary folate/vitamin B exposure, the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR), and epigenetic regulation of the genome via DNA methylation. Previously, it has been shown that the common c.677C > T polymorphism in MTHFR influences global DNA methylation status through a direct interaction with folate status and (indirectly) with total homocysteine (tHcy) levels. To build on that and other more-recent observations that have further highlighted associations among MTHFR c.677C > T, tHcy, and aberrations in DNA methylation, we investigated whether the interaction between mildly elevated plasma tHcy and the c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans. We used data on plasma tHcy levels, c.677C > T polymorphism, and site-specific DNA methylation levels for a total of 915 white women and 335 men from the TwinsUK registry ( n = 610) and the Rotterdam study ( n = 670). We performed methylome-wide association analyses in each cohort to model the interaction between levels of tHcy and c.677C > T genotypes on DNA methylation β values. Our meta-analysis identified 13 probes significantly associated with rs1801133 × tHcy levels [false-discovery rate (FDR) < 0.05]. The most significant associations were with a cluster of probes at the AGTRAP-MTHFR-NPPA/B gene locus on chromosome 1 (FDR = 1.3E-04), with additional probes on chromosomes 2, 3, 4, 7, 12, 16, and 19. Our top 2 hits on chromosome 1 were functionally associated with variability in expression of the TNF receptor superfamily member 8 ( TNFRSF8) gene/locus on that chromosome. This is the first study, to our knowledge, to provide a direct link between perturbations in 1-carbon metabolism, through an interaction of tHcy and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation.-Nash, A. J., Mandaviya, P. R., Dib, M.-J., Uitterlinden, A. G., van Meurs, J., Heil, S. G., Andrew, T., Ahmadi, K. R. Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans.

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“…Maternal GDM is associated with genome-wide DNA methylation changes in the placenta and cord blood of the exposed offspring 2 . Further studies have revealed that methylation at multiple genes/loci regulated by maternal GDM is responsible for the transmission of GDM effects to the next generation 37 . Another study revealed that GDM has epigenetic effects on genes that are preferentially involved in metabolic disease pathways, with consequences to fetal development 2 .…”

Section: Maternal Factors Affecting Inborn Errors Of Metabolism (Iemsmentioning

confidence: 99%

Integrated metabolome analysis reveals novel connections between maternal fecal metabolome and the neonatal blood metabolome in women with gestational diabetes mellitus

Zhao¹,

Ge²,

Li³

et al. 2020

Sci Rep

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Gestational Diabetes Mellitus (GDM), which is correlated with changes in the gut microbiota, is a risk factor for neonatal inborn errors of metabolism (ieMs). Maternal hyperglycemia exerts epigenetic effects on genes that encode IEM-associated enzymes, resulting in changes in the neonatal blood metabolome. However, the relationship between maternal gut microbiota and the neonatal blood metabolome remains poorly understood. this study aimed at understanding the connections between maternal gut microbiota and the neonatal blood metabolome in GDM. 1H-NMR-based untargeted metabolomics was performed on maternal fecal samples and targeted metabolomics on the matched neonatal dry blood spots from a cohort of 40 pregnant women, including 22 with GDM and 18 controls. Multi-omic association methods (including Co-Inertia Analysis and Procrustes Analysis) were applied to investigate the relationship between maternal fecal metabolome and the neonatal blood metabolome. Both maternal fecal metabolome and the matched neonatal blood metabolome could be separated along the vector of maternal hyperglycemia. A close relationship between the maternal and neonatal metabolomes was observed by multi-omic association approaches. Twelve out of thirty-two maternal fecal metabolites with altered abundances from 872 1H-NMR features (Bonferroni-adjusted P < 0.05) in women with GDM and the controls were identified, among which 8 metabolites contribute (P < 0.05 in a 999-step permutation test) to the close connection between maternal and the neonatal metabolomes in GDM. Four of these eight maternal fecal metabolites, including lysine, putrescine, guanidinoacetate, and hexadecanedioate, were negatively associated (Spearman rank correlation, coefficient value < −0.6, P < 0.05) with maternal hyperglycemia. Biotin metabolism was enriched (Bonferroni-adjusted P < 0.05 in the hypergeometric test) with the four-hyperglycemia associated fecal metabolites. the results of this study suggested that maternal fecal metabolites contribute to the connections between maternal fecal metabolome and the neonatal blood metabolome and may further affect the risk of IEMs. Gestational diabetes mellitus (GDM) has attracted worldwide public health concern due to its adverse maternal, fetal and neonatal outcomes. GDM is a serious pregnancy complication with various risk factors 1 , including overweight, obesity, a family history of diabetes, advanced maternal age, etc. GDM has been linked with an increased risk of inborn errors of metabolism (IEMs) in offspring 2,3. IEMs are caused by inherited genetic defects and can be influenced by environmental stimuli 4. Accumulating evidence suggests that maternal hyperglycemia is associated

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Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Cited by 96 publications

References 62 publications

Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus

Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus

Interaction between plasma homocysteine and the MTHFR C.677C > T polymorphism is associated with site‐specific changes in DNA methylation in humans

Integrated metabolome analysis reveals novel connections between maternal fecal metabolome and the neonatal blood metabolome in women with gestational diabetes mellitus

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