Maternal Pregestational BMI Is Associated With Methylation of the PPARGC1A Promoter in Newborns

Abstract

We explored peroxisome proliferator‐activated receptor‐γ co‐activator 1α gene (PPARGC1A), peroxisome proliferator‐activated receptor‐γ gene (PPARG), and transcription factor A mitochondrial gene (Tfam) promoter DNA methylation in newborns between both extremes of abnormal fetal growth: Small (SGA) and large for gestational age (LGA) in relation to the mother's characteristics. We further sought for the association of rs9930506 variant at FTO gene and the promoter patterns of DNA methylation in the aforementioned genes, in relation to the offspring's birth weight. In a cross‐sectional study, 88 healthy pregnant women and their babies were included. According to the offspring birth weight, there were 57 newborns with appropriate weight for gestational age (AGA), 17 SGA, and 14 LGA. After bisulphite treatment of umbilical cord genomic DNA, a real‐time methylation‐specific PCR was used to determine the promoter methylation status in selected CpGs. Promoter methylated DNA/unmethylated DNA ratio, expressed as mean ± s.e., was 0.82 ± 0.15 (45% of alleles) for PPARGC1A, and 0.0044 ± 0.0006 (0.4% of alleles) for Tfam. PPARG promoter was almost 100% methylated in all samples. In univariate analysis, there was no association among characteristics of the newborn and gene promoter methylation. None of the maternal features were related with the status of promoter methylation, except for a positive correlation between maternal BMI and PPARGC1A promoter methylation in umbilical cord (Pearson correlation coefficient r = 0.41, P = 0.0007). Finally, FTO rs9930506 AA homozygous in the LGA group showed decreased levels of methylated PPARGC1A in comparison with AG + GG genotypes and AGA and SGA infants. In conclusion, our findings suggest a potential role of promoter PPARGC1A methylation in metabolic programming.

Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective

“…In a recent work, Godfrey et al (2011) measured the methylation status of 68 CpGs 5' from five candidate genes in umbilical cord tissue DNA from healthy neonates, and found that methylation higher levels within promoter region of retinoid X receptor-a (RXRA) gene, measured at birth, was strongly correlated with greater adiposity in later childhood (Godfrey et al 2011). A positive correlation between maternal BMI and promoter methylation in peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PPARGC1A), a gene encoding a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) α and У, playing an essential role in energy homeostasis, was observed when analyzing promoter genomic DNA from umbilical cord newborns (Gemma et al 2009). …”

“…The obesity risk allele of FTO has been associated with higher methylation of sites within the first intron of the FTO gene, suggesting an interaction between genetic and epigenetic factors (Gemma et al 2009). Moreover, Almén et al (2012) determined the methylation profile on a genome-wide scale by sampling DNA from peripheral whole blood in female preadolescents.…”

IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator–activated receptor-γ coactivator-1α in rats

“…Recently, the DNA methylation level of PGC-1α promoter in umbilical cord has been found to positively correlate with maternal pregestational BMI (24); moreover, the PGC-1α methylation level is increased in the muscle of low-birth-weight adults (19,25), and 5-d overfeeding may influence the DNA methylation of PGC-1α in a birth-weight-dependent manner (19); besides, maternal methyl donor-deficient diet leads to PGC-1α protein hypomethylation in the liver of the pups with subsequent impairment of fatty acid oxidation (26), suggesting that both Articles prenatal and postnatal nutritional status may play a crucial role in metabolic programing through the epigenetic modification of PGC-1α. In our study, the methylation level of CpG sites -787 and -803 of PGC-1α promoter was higher in the liver and muscle of CG-IUGR rats while the methylation level of other CpG sites was comparable between the groups, and the methylation level of specific CpG sites was positively correlated with fasting insulin level.…”

Fetal metabolic programming and epigenetic modifications: a systems biology approach

“…Emerging data from human studies shed light on the association between birth weight, epigenetic modifications, and risk of developing MS-related phenotypes in later life. For instance, we explored the status of promoter DNA methylation of three key genes related with MS (PPARGC1A, PPARG, and TFAM) in newborns between both extremes of abnormal fetal growth and their relationship to the mother's prepregnant characteristics (40). Of note, we observed that promoter methylation of PPARGC1A in umbilical cord of newborns was positively correlated with maternal BMI.…”

“…For instance, H3K4Me3 levels around PER1, CLOCK, and BMAL promoters are highly correlated (R: 0.69, P < 0.0000005 and R: 0.68, P < 0.00002, respectively). Finally, this process seems to be modulated by the homozygosity for the more replicated obesity-associated risk allele of fat mass and obesity associated (FTO), the rs9930506 A, as we had reported for the PPARGC1A (PGC1A) promoter (40).…”