DNA Methylation Reorganization of Skeletal Muscle-Specific Genes in Response to Gestational Obesity

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 musclespecific 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.

Network Physiology of Exercise: Vision and Perspectives

“…In recent years, the Network Physiology framework has been utilized in various fields of basic Physiology and Clinical Medicine, including multiple organ failure and sepsis in critically ill patients (Asada et al, 2016;Moorman et al, 2016), neonatal intensive care (Lavanga et al, 2020;Lucchini et al, 2020), liver disease (Tan et al, 2020), epilepsy and neurological disorders (Lin et al, 2020), diabetes and obesity (Podobnik et al, 2020;Prats-Puig et al, 2020), cancer (Liu et al, 2020), or psychiatry (Bolton et al, 2020), and has the potential for broad applications in the field of Exercise Physiology and Sports Medicine to uncover how the key physiological systems interact pairwise, that is, which links are the major mediators in a given network and how these links adjust their strength with accumulation of fatigue, after a training intervention, or in response to a certain pathological condition (e.g., musculoskeletal injury and neurodegenerative disease).…”

The New Field of Network Physiology: Building the Human Physiolome

“…New computational and analytical approaches are needed to extract information from complex data, to infer transient interactions between dynamically changing systems, and to quantify global behavior at the organism level generated by networks of interactions that are function of time. In fact, in recent years, we have already witnessed the broad impact of introducing novel concepts and methods derived from modern statistical physics and network theory to biology and medicine, shifting the paradigm from reductionism to a new integrative framework essential to address fundamentally new problems in systems biology (Yao et al, 2019;Prats-Puig et al, 2020;Corkey and Deeney, 2020;Rizi et al, 2021;Barajas-Martínez et al, 2020), neuroscience (Castelluzzo et al, 2020;Pa¨eske et al, 2020;Fesce, 2020;Stramaglia et al, 2021), physiology (Podobnik et al, 2020;Zmazek et al, 2021), clinical medicine (Loscalzo and Barabasi, 2011;Delussi et al, 2020;Li et al, 2020;Liu et al, 2020;McNorgan et al, 2020;Tan et al, 2020;Haug et al, 2021;Liu et al, 2021) and even drug discovery (Hopkins, 2008). A central focus of research within this integrative framework is the interplay between structural connectivity and functional dependency, a key problem in neuroscience, brain research (Bullmore and Sporns, 2009;Gallos et al, 2012;Rothkegel and Lehnertz, 2014;Liu et al, 2015a;Bolton et al, 2020;Wang and Liu, 2020) and human physiology (Pereira-Ferrero et al, 2019;Lavanga et al, 2020;Barajas-Martínez et al, 2021;Gao et al, 2018;Balagué et al, 2020;Porta et al, 2017;Lioi et al, ...…”

Recent progress in epigenetics of obesity

“…These findings suggest that HOX genes are subject to differential epigenetic regulation in skeletal muscle and HDMCs in aged humans, and increased physical activity may help prevent these changes. Prats-Puig et al [ 61 ] performed DNAm measurements in 16 pregnant women (8 each for obese subjects and controls) to investigate whether gestational obesity was associated with DNAm changes in skeletal muscle-specific genes in umbilical cord tissue. Identification analysis reported 38 differentially methylated CpG loci in four skeletal muscle-specific genes: contractility, structure, actin, and myogenesis.…”