While some research takes us down well-worn paths, some scientists like to dust off their hiking shoes and take the road less traveled! This includes researchers led by Bastiaan Heijmans (Leiden University Medical Center, The Netherlands), Tobias Uller (Lund University, Sweden), and L.H. Lumey (Columbia University Medical Center, New York, USA), whose collaborative work aims to understand how prenatal adversity causes long-term physiological changes.
Altered DNA methylation levels represent an important mediating mechanism, although how the prenatal environment influences DNA methylation signatures remains relatively unknown. In brief, there exist two principal pathways by which plasticity can mediate the establishment of an epigenetic signature; either adverse conditions upset the establishment/maintenance of embryo DNA methylation or modified DNA methylation patterns try to match embryo phenotype to the environment. However, a new study has traveled down a different path to prove a hypothesis that random variations in DNA methylation contribute to the probability of embryo survival via epigenetic selection, rather than epigenetic plasticity.
Here are the landmarks on the path taken by the authors:
- The generation of testable predictions employed an extended computational mechanistic model that simulates transcription factor (TF) binding and DNA re-methylation dynamics in early-stage embryos
- This stochastic model analyzes 50-cell pre-implantation embryos, each containing 75 independent genes, with one TF per gene and ten CpG dinucleotides per TF binding site
- The team then compared epigenetic plasticity and epigenetic selection by modeling target genes that respond plastically or influence survival with or without maternal adversity
- Their model highlights random epigenetic variation between embryos and predicts that epigenetic variants that increase embryo survival will be more common in embryos suffering adverse conditions
- To test for this epigenetic selection signature, the authors assessed a human cohort exposed to famine during the Dutch Hunger Winter
- Assessment of CpGs associated with famine exposure uncovered empirical evidence for reduced DNA methylation variance
- Overall, the discovery of this DNA methylation signature within a population represents a signature of selection during prenatal development
Let’s hear from the leaders of this study on this new path:
“We know that a lack of nutrition decreases the likelihood of an embryo surviving. Our new study indicates that surviving famine in the uterus hinged on having a DNA methylation pattern allowing continued growth of the embryo in spite of limited resources. But those same methylation patterns may have adverse health effects much later in life,” says senior co-author Bas Heijmans.
“We have always struggled to explain how early embryos would be able to modify specific epigenetic marks in response to nutrition. It is fascinating that selective survival based on random epigenetic variation fits the data best”, says senior co-author Tobias Uller.
“These findings have often been interpreted as conclusive proof of fetal adaptations in the womb that will lead to adult disease if the adult environment changes for the better. But our findings point to a different mechanism”, says senior co-author L.H. Lumey, the principal investigator of the Dutch Hunger Winter Families study.