Metabolic Programming of <i>MEST</i> DNA Methylation by Intrauterine Exposure to Gestational Diabetes Mellitus

Hajj, Nady El; Pliushch, Galyna; Schneider, Eberhard; Dittrich, Marcus; Müller, Tobias; Korenkov, Michael; Aretz, Melanie; Zechner, Ulrich; Lehnen, H; Haaf, Thomas

doi:10.2337/db12-0289

Cited by 227 publications

(225 citation statements)

References 42 publications

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“…This model is supported by our EMSA data demonstrating impaired SOX6 binding to a MEST promoter template with adjacent CpG methylation. Our findings therefore extend published observations that obesity significantly associates with decreased methylation levels at the MEST gene (Soubry et al, 2015), that MEST hypomethylation is linked to metabolic programming in offspring with a background in gestational diabetes (El Hajj et al, 2013), and that there is an inverse relationship between MEST CpG methylation levels and body composition measures, such as waist circumference and body mass index (Carless et al, 2013).…”

Section: Discussionsupporting

confidence: 77%

The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis

et al. 2016

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An association between impaired fetal growth and the postnatal development of obesity has been established. Here, by comparing adipocytes differentiated from mesenchymal stem cells (MSCs) taken from the umbilical cord and derived from normal and growth-restricted neonates, we identified the transcription factor SOX6 as highly expressed only in growth-restricted individuals. We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST. We further show that SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis. The upstream regulatory region of the MEST gene in MSCs from growth-restricted subjects harbors hypomethylated CpGs next to SOX6 binding motifs, and we found that SOX6 binding is impaired by adjacent CpG methylation. In summary, we report that SOX6 is a novel regulator of adipogenesis synergizing with epigenetic mechanisms.

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Section: Discussionsupporting

confidence: 77%

The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis

et al. 2016

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“…This is an important result, as it has been shown that in utero epigenetic alterations in the placenta and fetal blood can program metabolic disease in the offspring (45,46). However, more detailed studies are required to investigate whether epigenetic mechanisms affect the lipidemic profile observed in the fetoplacental unit in response to a hypercholanemic environment.…”

Section: Discussionmentioning

confidence: 99%

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Papacleovoulou¹,

Abu‐Hayyeh²,

Nikolopoulou³

et al. 2013

J. Clin. Invest.

107

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The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.

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“…Interestingly, LEPTIN promoter methylation is higher in the placentas of males than females (+2.3 percentage point difference). A German team studied DNA methylation of 16 candidate regions in women with diet-or insulin-treated GDM (El Hajj et al, 2013). They found a decrease in placental DNA methylation in four genes and two repeated regions.…”

mentioning

confidence: 99%

Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism

Tarrade

Panchenko

Junien

et al. 2015

Journal of Experimental Biology

202

149

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The recent and rapid worldwide increase in non-communicable diseases challenges the assumption that genetic factors are the primary contributors to such diseases. A new concept of the 'developmental origins of health and disease' (DOHaD) is at stake and therefore requires a paradigm shift. Maternal obesity and malnutrition predispose offspring to develop metabolic syndrome, a vicious cycle leading to transmission to subsequent generation(s), with differences in response and susceptibility according to the sex of the individual. The placenta is a programming agent of adult health and disease. Adaptations of placental phenotype in response to maternal diet and metabolic status alter fetal nutrient supply. This implies important epigenetic changes that are, however, still poorly documented in DOHaD studies, particularly concerning overnutrition. The aim of this review is to discuss the emerging knowledge on the relationships between the effect of maternal nutrition or metabolic status on placental function and the risk of diseases later in life, with a specific focus on epigenetic mechanisms and sexual dimorphism. Explaining the sex-specific causal variables and how males versus females respond and adapt to environmental perturbations should help physicians and patients to anticipate disease susceptibility.KEY WORDS: DOHaD, Fetal programming, Placenta, Sex, Nutrition, Obesity, Maternal environment, Gestation Introduction: developmental origins of health and diseaseThe recent and rapid worldwide increase in non-communicable diseases (NCDs) challenges the assumption that genetic factors are the primary contributors to such diseases (McAllister et al., 2009). The 'developmental origins of health and disease' (DOHaD) paradigm states that the environment during the periconception, gestation and lactation periods shapes the developing individuals, leading, in the case of a deleterious environment, to a predisposition to adult-onset diseases. This theory was popularised by D. J. Barker in the early 1990s (Barker, 1990) but the question had already been raised in earlier studies. In the 1960s and 1970s, different experiments on diverse mammalian species (rat, mouse, guinea pig, pig, etc.) showed that a reduction of maternal calorie or protein intake during pregnancy and lactation affects the growth capacity and cognitive ability of the offspring (reviewed in Roeder and Chow, 1972;McCance, 1976). Later, this concept was extended to phenotype in general, with a strong implication for quantitative traits in agriculture. An increasing number of studies pointed to the fact that maternal environment in cattle was an important parameter to fully express the genetically highly selected potential of the animals (Wallace et al., 2010; Jammes et al., 2011;Tanghe et al., 2014).Male and female susceptibility to NCDs is well described. It appears that in the DOHaD context, the same environmental exposure may affect the long-term health of the offspring with a discrepancy between males and females in terms of the timing, onset ...

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Metabolic Programming of MEST DNA Methylation by Intrauterine Exposure to Gestational Diabetes Mellitus

Cited by 227 publications

References 42 publications

The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis

The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism

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