Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors

Lesseur, Corina; Armstrong, David A.; Paquette, Alison G.; Koestler, Devin C.; Padbury, Jamés F.; Marsit, Carmen J.

doi:10.1016/j.mce.2013.07.024

Cited by 94 publications

(98 citation statements)

References 56 publications

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“…Lesseur et al found that small for gestational age (SGA) newborns had higher DNAm levels in LEP promoter region (see genomic location in Fig. S2 -Lesseur) in cord blood cells 34 ; directionally concordant with our observation that higher DNAm at LEP is associated with lower leptin levels and lower birth weight. This is also consistent with previous functional studies of leptin expression regulation in adipocytes during differentiation: pre-adipocytes showed high DNAm levels, LEP promoter was almost fully unmethylated in mature adipocytes, and demethylation of specific CpG sites in LEP promoter was essential for leptin expression.…”

Section: Discussionsupporting

confidence: 91%

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

et al. 2015

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Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS 10 ) and showed it was an adequate instrumental variable (b D 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE D 0.007; P D 7.8 £ 10 ¡11 ; N D 467). A higher GRS 10 was associated with lower methylation levels at cg12083122 located near LEP (b D ¡0.072 unit per additional risk allele; SE D 0.04; P D 0.05; N D 166). Direction and effect size of association between the instrumental variable GRS 10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (b D ¡0.17 log of cord blood leptin per unit; SE D 0.07; P D 0.01; N D 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

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Section: Discussionsupporting

confidence: 91%

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

et al. 2015

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“…18 For example, in utero exposure to famine and gestational diabetes has been associated with offspring LEP promoter hypermethylation in blood of adults 11 and placental LEP hypermethylation, 19 respectively. According to Lesseur et al, 12 cord blood LEP methylation was higher in small for gestational age infants and lower in infants born to pre-pregnancy obese mothers. Modifications in the profile of leptin in early life may contribute to the lower expression of appetite regulators, alter fetal neural development, and, in the end, alter the susceptibility to obesity and metabolic disorders in adulthood.…”

Section: Discussionmentioning

confidence: 97%

“…LEP promoter DNA methylation has been linked to adverse pregnancy outcomes and is plausibly involved in fetal metabolic programming. 12 Another metabolic gene that can be affected by maternal nutrition is the retinoid X receptor a (RXRA) gene, which is known to be involved in insulin sensitivity, adipogenesis, and fat metabolism. Lower maternal carbohydrate intake in early pregnancy was associated with higher RXRA cord blood methylation and with greater offspring's adiposity (fat mass and percentage fat mass) in 9-year old children.…”

Section: Introductionmentioning

confidence: 99%

Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation

et al. 2016

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Maternal nutrition is critically involved in the development and health of the fetus. We evaluated maternal methyl-group donor intake through diet (methionine, betaine, choline, folate) and supplementation (folic acid) before and during pregnancy in relation to global DNA methylation and hydroxymethylation and gene specific (IGF2 DMR, DNMT1, LEP, RXRA) cord blood methylation. A total of 115 mother-infant pairs were enrolled in the MAternal Nutrition and Offspring's Epigenome (MANOE) study. The intake of methylgroup donors was assessed using a food-frequency questionnaire. LC-MS/MS and pyrosequencing were used to measure global and gene specific methylation, respectively. Dietary intake of methyl-groups before and during pregnancy was associated with changes in LEP, DNMT1, and RXRA cord blood methylation. Statistically significant higher cord blood LEP methylation was observed when mothers started folic acid supplementation more than 6 months before conception compared with 3-6 months before conception (34.6 § 6.3% vs. 30.1 § 3.6%, P D 0.011, LEP CpG1) or no folic acid used before conception (16.2 § 4.4% vs. 13.9 § 3%, P D 0.036 for LEP CpG3 and 24.5 § 3.5% vs. 22.2 § 3.5%, P D 0.045 for LEP mean CpG). Taking folic acid supplements during the entire pregnancy resulted in statistically significantly higher cord blood RXRA methylation as compared with stopping supplementation in the second trimester (12.3 § 1.9% vs. 11.1 § 2%, P D 0.008 for RXRA mean CpG). To conclude, long-term folic acid use before and during pregnancy was associated with higher LEP and RXRA cord blood methylation, respectively. To date, pregnant women are advised to take a folic acid supplement of 400 mg/day from 4 weeks before until 12 weeks of pregnancy. Our results suggest significant epigenetic modifications when taking a folic acid supplement beyond the current advice.

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“…Studies linking genetic variability and race or ethnicity and epigenetic mechanisms have been limited. Where studies have examined genetic variation and epigenetics, they have generally focused on candidate genes involved in metabolism of folate or the pathways involved in the epigenetic mechanism, or in some cases on specific relationships between genetic variants within a gene and their epigenetic consequences (Bromer et al, 2013;Klengel et al, 2013;Lesseur et al, 2013;Paquette et al, 2013). There have been suggestions of differences in DNA methylation by race and ethnicity (Terry et al, 2008), although strong examinations that can control for the confounding factors of environment and race have not yet been undertaken, and are an important area to consider.…”

Section: Additional Factors Influencing Epigeneticsmentioning

confidence: 99%

Influence of environmental exposure on human epigenetic regulation

Marsit

2015

Journal of Experimental Biology

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195

119

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Environmental toxicants can alter epigenetic regulatory features such as DNA methylation and microRNA expression. As the sensitivity of epigenomic regulatory features may be greatest during the in utero period, when critical windows are narrow, and when epigenomic profiles are being set, this review will highlight research focused on that period. I will focus on work in human populations, where the impact of environmental toxicants in utero, including cigarette smoke and toxic trace metals such as arsenic, mercury and manganese, on genome-wide, gene-specific DNA methylation has been assessed. In particular, arsenic is highlighted, as this metalloid has been the focus of a number of studies and its detoxification mechanisms are well understood. Importantly, the tissues and cells being examined must be considered in context in order to interpret the findings of these studies. For example, by studying the placenta, it is possible to identify potential epigenetic adaptations of key genes and pathways that may alter the developmental course in line with the developmental origins of health and disease paradigm. Alternatively, studies of newborn cord blood can be used to examine how environmental exposure in utero can impact the composition of cells within the peripheral blood, leading to immunological effects of exposure. The results suggest that in humans, like other vertebrates, there is a susceptibility for epigenomic alteration by the environment during intrauterine development, and this may represent a mechanism of plasticity of the organism in response to its environment as well as a mechanism through which long-term health consequences can be shaped.

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Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors

Cited by 94 publications

References 56 publications

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation

Influence of environmental exposure on human epigenetic regulation

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