Abstract
The goals were to investigate in umbilical cord tissue if gestational obesity: (1) was associated with changes in DNA methylation of skeletal muscle-specific genes; (2) could modulate the co-methylation interactions among these genes. Additionally, we assessed the associations between DNA methylation levels and infant’s variables at birth and at age 6. DNA methylation was measured in sixteen pregnant women [8-gestational obesity group; 8-control group] in umbilical cord using the Infinium Methylation EPIC Bead Chip microarray. Differentially methylated CpGs were identified with Beta Regression Models [false discovery rate (FDR) < 0.05 and an Odds Ratio > 1.5 or < 0.67]. DNA methylation interactions between CpGs of skeletal muscle-specific genes were studied using data from Pearson correlation matrices. In order to quantify the interactions within each network, the number of links was computed. This identification analysis reported 38 differential methylated CpGs within skeletal muscle-specific genes (comprising 4 categories: contractibility, structure, myokines, and myogenesis). Compared to control group, gestational obesity (1) promotes hypermethylation in highly methylated genes and hypomethylation in low methylated genes; (2) CpGs in regions close to transcription sites and with high CpG density are hypomethylated while regions distant to transcriptions sites and with low CpG density are hypermethylated; (3) diminishes the number of total interactions in the co-methylation network. Interestingly, the associations between infant’s fasting glucose at age 6 and MYL6, MYH11, TNNT3, TPM2, CXCL2, and NCAM1 were still relevant after correcting for multiple testing. In conclusion, our study showed a complex interaction between gestational obesity and the epigenetic status of muscle-specific genes in umbilical cord tissue. Additionally, gestational obesity may alter the functional co-methylation connectivity of CpG within skeletal muscle-specific genes interactions, our results revealing an extensive reorganization of methylation in response to maternal overweight. Finally, changes in methylation levels of skeletal muscle specific genes may have persistent effects on the offspring of mothers with gestational obesity.
Highlights
Excessive gestational weight gain is related to offspring obesity and related metabolic disorders, independently of pre-pregnancy body mass index (Wrotniak et al, 2008; Olson et al, 2009; Reynolds et al, 2010; Vickers, 2014)
Among the differently methylated individual CpG sites identified in umbilical cord tissue between mother with and without gestational obesity and according to only FDR criteria we found 6 CpGs related to contractile function, 65 related to structure, 28 CpG related to myokines and 16 related to myogenesis of skeletal muscle (Supplementary Table 2)
Except for gene CDH15-2, the effect of gestational obesity on DNA methylation might depend on initial methylation levels: compared to control group, gestational obesity promotes a hypermethylation effect in highly methylated genes (Supplementary Figure 1A and Supplementary Table 3), with a mean increase in methylation of 11.97%, and a hypomethylation effect in low methylated genes, with a mean decrease in methylation of 58.54%
Summary
Excessive gestational weight gain is related to offspring obesity and related metabolic disorders, independently of pre-pregnancy body mass index (Wrotniak et al, 2008; Olson et al, 2009; Reynolds et al, 2010; Vickers, 2014). Studies in rats showed that offspring born to mothers fed an obesogenic diet during pregnancy exhibit reduced skeletal muscle cross-sectional area and fiber number. These structural defects led to impaired muscle contractility (Bayol et al, 2005) and impaired insulin signaling pathway and mitochondrial function (Shelley et al, 2009). Defects in the formation of skeletal muscle in utero can lead to metabolic complications into adult life (Bayol et al, 2014) as there is no increase in muscle fiber numbers after birth (White et al, 2010)
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