Variation in the human placental epigenome in response to environmental, genetic and gestational effects: implications for the study of adverse pregnancy outcomes. (#15)
The Developmental Origin of Health and Disease (DoHAD) hypothesis predicts that many adult diseases have their origin in utero. This was first proposed to describe the observed link between low birth weight and increased risk of cardiovascular disease in later life. Given its location at the fetomaternal interface, the placenta likely plays a critical role in mediating environmental effects associated with this programming phenomenon, potential via changes in epigenetic (eg. DNA methylation) profile.
Mounting evidence suggests an elevated level of inter-individual variation in DNA methylation in full term placenta relative to somatic tissues. However, mechanisms underlying this variation remain unclear, as does the potential link between altered methylation and adverse pregnancy outcomes. We speculated that this variation results from a combination of both genetic and environmental factors, which combine during pregnancy to modulate the level of methylation present at specific gene promoters to alter gene expression.
In order to test this we carried out 3 separate studies.
- Firstly we measured DNA placental methylation profile during each of first, second and third trimester pregnancies. We identified large-scale differences in DNA methylation levels across gestation, with an overall progressive increase from first to third trimester. The most differentially methylated genes included many immune regulators, reflecting the change in placental immuno-modulation as pregnancy progresses. We also detected increased inter-individual variation in the third trimester relative to first and second, supporting an accumulation of environmentally induced (or stochastic) changes in DNA methylation pattern.
- In order to test the relative effects of genes and environment to development of the placental epigenome, we profiled DNA methylation in placentas from 16 twin pregnancies, collected as part of the Peri/Postnatal Epigenetic Twins study (PETS). Studying twins allows the relative contributions of genetic and environmental influences to DNA methylation profile to be estimated. Cluster analysis revealed that sex was the biggest determinant of overall placental methylation profile. Whereas twin placentas generally show a higher correlation in methylation than non-related individuals, some exceptions were noted. Monozygotic twins showed a higher correlation than dizygotic twins, highlighting the contribution of genetic factors to the establishment of the placental epigenome.
- Finally, we measured the potential for changes in placental DNA methylation at specific genes to contribute to altered levels of circulating vitamin D in the neonate. We identified placenta-specific methylation of the gene encoding the major catabolic enzyme of active vitamin D (CYP24A1) and demonstrated a functional role for this epigenetic mark in non-placental cells. However, an analysis of the relationship between maternal circulating vitamin D, neonatal vitamin D in twins and placental methylation measured at birth did not support a relationship between epigenetic status of this gene and neonatal vitamin D levels.
In combination, our data confirm that the unique placental epigenome in humans is subject to a variety of different influences throughout pregnancy. The resulting functional relevance to the developing pregnancy is not straightforward and will require case-by-case examination with appropriate functional and other studies.