Birth weight discordance, gene expression, and DNA methylation: A review of epigenetic twin studies

Abstract

BackgroundBirth weight is considered as an important indicator of environmental conditions during prenatal development. Molecular mechanisms, including epigenetic modifications play an important role in the bodys adaptation to ever changing environmental conditions. As twin design can be used to identify the role of environmental contributions while controlling for genetic variations, numerous monozygotic twin studies have shown how adverse prenatal environment can lead to birth weight discordance (BWD). ObjectiveAn overview of the literature about epigenetic modifications associated with BWD in twins. MethodWe searched PubMed and Ovid MEDLINE(R) databases and included 34 papers that studied associations between BWD and DNA (hydroxy)methylation or gene expression in easily accessible samples of twin pregnancies or peripheral tissues of twins later in life. ResultsResearchers and clinicians still lack consensus on BWD thresholds, which vary between 15-30% depending on the type of placentation and gestational age. The gene expression twin studies measured mostly metabolism-related candidate genes in placental tissues. Only small-scale twin studies measured BWD associated gene expression patterns on genome-wide level using neonatal cells. Most DNA methylation twin studies used epigenome-level analyses, but the analysed tissue and age of sampling varied widely (blood from adults, saliva samples from children, placenta at delivery). Importantly, a handful of growth-related genes (e.g., IGF2, LEPROT, ADRB3, GLUT3) were associated with BWD. ConclusionTranscriptional changes of genes coding for placental glucose transporters and hypoxia-induced proteins possibly reflect compensatory processes in twin pregnancies. Epigenetic regulation of growth-related genes in the offspring offer a relevant mechanism to counterbalance adverse prenatal environment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/625968v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@e20978org.highwire.dtl.DTLVardef@1dbc274org.highwire.dtl.DTLVardef@bb8f40org.highwire.dtl.DTLVardef@1b9cdcc_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract/Figure 1.C_FLOATNO (Created in https://BioRender.com) Although monozygotic twins have almost the same DNA sequence (see double stranded DNA helix in the middle), there are many molecular regulatory processes differentially affected by certain in utero environmental factors (such as unequal blood supply). Therefore, in a proportion of twin pregnancies, the intrauterine growth of the developing embryos is uneven, resulting in substantial birth weight difference. The underlying epigenetic alterations, such as DNA methylation changes can be long-lasting, measurable after birth and may serve as biomarkers reflecting risk for later health problems. An important technical feature is that the DNA molecule is quite stable and the methyl groups are attached covalently (shown as Me), hence methylation analyses are wide-spread in medical studies. C_FIG