Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta. [Research Support, N.I.H., Extramural]

Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 05/2011; 6(5):566-72. DOI: 10.4161/epi.6.5.15236
Source: PubMed


Birthweight has been associated with a number of health outcomes throughout life. Crucial to proper infant growth and development is the placenta, and alterations to placental gene function may reflect differences in the intrauterine environment which functionally contribute to infant growth and may ultimately affect the child's health. To examine if epigenetic alteration to the glucocorticoid receptor (GR) gene was linked to infant growth, we analyzed 480 human placentas for differential methylation of the GR gene exon 1F and examined how this variation in methylation extent was associated with fetal growth. Multivariable linear regression revealed a significant association (p < 0.0001) between differential methylation of the GR gene and large for gestational age (LGA) status. Our work is one of the first to link infant growth as a measure of the intrauterine environment and epigenetic alterations to the GR and suggests that DNA methylation may be a critical determinant of placental function.

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Available from: Carolyn E Banister
    • "For example, DNA methylation levels at the IGF2 gene were reported to be significantly lower in adults who were in utero during the Dutch Hunger Winter Famine (1944–1945) when compared to same-sex siblings in utero unexposed to famine (Heijmans et al., 2008). Other candidate gene studies have also reported birth weight related methylation differences in imprinted genes that play a role in fetal growth, such as IGF2 and H19 (Hoyo et al., 2012; Steegers–Theunissen et al., 2009) and in nonimprinted genes such as the glucocorticoid receptor NR3C1 (Filiberto et al., 2011; Mulligan et al., 2012). More recently, epigenome-wide association studies (EWAS) have been performed for birth weight using the Infinium HumanMethy- lation27 BeadChip (Infinium 27K; Adkins et al., 2012; Banister et al., 2011; Fryer et al., 2011; Straughen et al., 2015) and the Infinium HumanMethylation450 BeadChip (Infinium 450K; Engel et al., 2014; Simpkin et al., 2015) methylation platforms (Illumina Inc, San Diego, CA). "
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    ABSTRACT: Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to pre-disposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10-8), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.
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    • "Although SEPP1 is expressed and active in the placenta (Kasik and Rice 1995), there have been no examinations of SEPP1 methylation or its relationship to Hg in the placenta. The placenta is active during development, and variation in placental methylation at various genes has been associated with fetal growth and development and neuro behavior (Banister et al. 2011; Bromer et al. 2012; Filiberto et al. 2011; Marsit et al. 2012a, 2012b; Wilhelm-Benartzi et al. 2012). Thus, Hg-associated placental alterations may mediate exposure-associated neurobehavioral outcomes, even at exposure levels commonly identified in the population. "
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    • "Because certain classes of epigenetic marks, notably DNA and histone methylation, are stably maintained in mitotic and postmitotic cells, this " environmental epigenetic " hypothesis provides a candidate mechanism for the enduring influences of the social environment on neurodevelopment and mental health (Bateson et al., 2004; Feil & Fraga, 2011; Jirtle & Skinner, 2007; Meaney & Ferguson-Smith, 2010; Zhang & Meaney, 2010). Support for this hypothesis is derived from studies of the methylation of a glucocorticoid receptor gene promoter that reveal stable associations between levels of DNA methylation and both pre-and postnatal adversity (Bromer , Marsit, Armstrong, Padbury, & Lester, 2013; Filiberto et al., 2011; Hompes et al., 2013; Labonte et al., 2012; Mc- Gowan et al., 2009; Mulligan, D'Errico, Stees, & Hughes, 2012; Oberlander et al., 2008; Perroud et al., 2011, 2014; Radtke et al., 2011; Steiger, Labonte, Groleau, Turecki, & Israel , 2013; Tyrka, Price, Marsit, Walters, & Carpenter, 2012). These findings emerge from studies using cells obtained from blood sampling as well as those involving postmortem human hippocampus, suggesting that environmental influences on epigenetic states of at least certain genomic regions are apparent across multiple tissues. "
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