Waddington’s epigenetic landscape is a classic metaphor for the role of epigenomics in development. In it, a cell becomes increasingly committed to a certain developmental trajectory as it acquires marks that poise it for later development.
Massive efforts have been undertaken to chart this unexplored landscape and discover the buried treasures of development. Much has been discovered about the waves of remodeling during embryonic pre-implantation but the post-implantation environment remains more of a mystery. Now it seems that for fetal development the treasures of trajectory lie in enhancers rather than promoters.
The talented team from Leiden University in the Netherlands that brought us insight into the Dutch Hunger Winter along with the along with the department of Embryology set out to chart the DNA methylation landscape of four healthy developing human tissues (amnion, muscle, adrenal and pancreas) using the 450K Array. They did this during the first and second trimester of gestation (at 9, 18 and 22 weeks). Here’s what they found:
- As early as 9 weeks into gestation, a tissue specific signature characterized by hypomethylated CpGs emerges.
- There is large scale DNA methylation remodeling between weeks 9 and 22 that correlates with altered transcription in which:
- Genes involved in general developmental programs are methylated and repressed.
- Genes involved in tissue specific-programs loss methylation and are activated.
- Interestingly, these methylation dynamics were associated with enhancers but not promoters.
The team also compared their results with those from external datasets: fetal datasets confirmed their results and adult tissue datasets showed a surprisingly high level of overlap, suggesting that not a lot changes at these sites after week 22. Ultimately, dynamic DNA methylation is critical for not only embryonic development, but also fetal, although it doesn’t appear to occur in distinct global waves in the fetus.
Co-first authors Roderick Slieker and Matthias Roost conclude, “Our research shows that epigenomic remodeling at enhancers keeps cells on track while traversing Waddington’s landscape. The next step is to identify genetic and environmental effects that perturb this remodelling during development and result in persistent epigenetic changes that influence disease risk later in life.”
Go and see why enhancers are a prime site for some epigenetic landscaping in PLoS Genetics, October 2015