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
- 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
- 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.
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.