DNA methylation in the human placenta and fetal growth (review)

Abstract

Throughout in utero development, the placenta plays a key role in controlling growth and development. The placenta acts not only as a gatekeeper of nutrient and waste exchange between mother and developing fetus, but also as a regulator of the intrauterine environment. Its functions can be influenced by the environment encountered throughout pregnancy, thereby altering the appropriate genetic programming needed to allow for appropriate fetal growth. Epigenetic alterations related to environmental exposures have been linked to aberrant fetal growth. DNA methylation, which is the best known DNA epigenetic modification, may provide an attractive mechanism linking environmental cues to placental pathology, with consequences for fetal growth and adult life. Alteration of the methylation patterns of genes expressed in the placenta has recently been found to modify gene expression and subsequently impair function of the placenta. Although there is strong evidence to demonstrate that the environment can affect the pattern of DNA methylation of the placenta during fetal development, a direct association between environmental conditions, methylation alterations and gene expression is difficult to confirm. DNA methylation in the placenta has mainly been investigated in the context of imprinted and non-imprinted genes transcription. Several environmental factors have also been assessed in regard to their association with changes to the epigenetic motives of embryonic and extraembryonic tissues and their impact on pregnancy outcome. In this review, we briefly present the available evidence regarding the role of DNA methylation patterns of the placenta on aberrant fetal growth.

Figure 1

Schematic representation of the imprinted regulation of the IGF2/H19 cluster. Maternal and paternal chromosomes are indicated. Vertical black bars are exons from the expressed allele; red vertical bars are exons from the silenced allele. The arrows show the direction of transcription (white arrows show active transcription from IGF2 P0, P2, P3, P4 and the H19 promoter; black arrow shows the non-imprinted P1 IGF2 promoter). Ovals represent the enhancers. The long arrowed lines indicate enhancer activity. Three known Differentially Methylated Regions (DMR) are presented as sets of triangles. Black triangles are methylated DMRs and white triangles are unmethylated regions. DMR upstream of H19, which harbors sequences known to bind to the zinc finger protein CTCF, if methylated on the paternal chromosome prevents binding with CTCF, allowing the IGF2 promoter to assess enhancers located downstream of H19, thereby expressing IGF2. On the maternal chromosome, the non-methylated H19 DMR is bound to CTCF, thus insulating the IGF2 promoter from the 3′ enhancers and allowing the H19 promoter unimpeded access to the enhancers. Maternal H19 is subsequently transcribed.

Figure 2

A potential link between environmental factors and aberrant fetal growth in the context of methylation modifications in the placenta. Environmental factors such as assisted reproduction techniques, alcohol, chemical agents, tobacco and malnutrition are capable of altering the epigenetic profile of several imprinted and non-imprinted genes expressed in the placenta. This event may influence the proper structure or function of the trophoblast and in turn affect fetal growth; however, the exact sequence of events requires further elucidation.