Two recent Nature papers made big strides in understanding mammalian embryonic DNA methylation. The Meissner and Eggan team from Harvard focused in on CpG dynamics and how they compare to mice, specifically in terms of parental contribution. While the Qian and Tang team from Bejing examined how DNAm effects the epigenetic embryonic landscape in terms of histone modifications and transposons.
Ever-Changing Embyronic CpGs
CpG dinucleotide modifications are pretty much fixed in adults, aside from certain diseases, and a the growing number of environmentally responsive loci. Embryos, however, have a huge amount of reprogramming going on. While this process is extensively studied in mice, not so much is known about how this works in humans.
Groups headed by Alexander Meissner and Kevin Eggan from the Broad Institute of MIT and Harvard University deployed reduced representation bisuflite sequencing (RRBS) to examine the CpG dynamics of over 1 million sites in human embryos and developed new genome-scale DNA methylation maps of embryonic development. Here’s how we compare up to mice:
- Human and mouse dynamics appear similar on a global scale, consiting mainly of hypomethylation with a few maintained states loacted in gene bodies.
- Methylation patterns from the mother differs in species-specific CpG island promoter sets that are outside of imprinting control regions (ICRs).
- Retrotransposons, a cousin of ICRs, also displayed differential regulation from maternal CpGs.
The resarchers found that parental contributions have differences in embryonic development, with paternal demethylation acting as a general feature in early mammalian embryonic development and the maternal contributions directing species-specific roles. While the EpiGenie team is left pondering a new perspective on John Steinbeck’s “Of Mice and Men”.
DNA Methylation Landscape of Developing Human Embryos
Building on the importance of DNA methylation in embryonic development, the next paper takes a look at how it interacts with the rest of the epigenetic landscape, like histone modifications, to ensure the proper developmental programming.
A research team led by Jie Qian and Fuchou Tang from Peking University in Beijing used both RRBS and whole-genome bisulphite sequencing (WGBS) to map out development of early embryos from the zygotic through to post-implantation stages. Here’s the lay of the land:
- As opposed to mice, in humans, most of the genome-wide demethylation is complete by the 2-cell stage.
- Paternal genomic demethylation happens much faster than in the maternal genome.
- The traditional promoter methylation/gene expression relationship grows during early embryonic development. peaking at post-implantation.
- Active genes marked by H3K4me3 in their promoters are not methylated in pluripotent embryonic stem cells.
- Retrotransposons in the genome aren’t demethylated as often as some evolutionalrily older elements.
Overall, this study showed new insights into thee methylation dynamics of human early embryos, how they relate to histone modifications and and how this effects regulation of gene expression and transposons.
The Molecular Landscape of Development
When it comes to the take home message of these two papers it seems that DNA methylation is a critical molecular program for development and allows for all the complexity that traditional genetic dogma doesn’t account for. The process is conserved in mammals, with some species-specific divergence occurring preferentially from the maternal inheritance, which may mean a lot for the world of environmental epigenetics. DNA methylation is shown here as a team player for regulating the genome and that transposons have an under-appreciated role in the regulation of gene expression, as well as larger scale processes, like the development of a human from a polymer of 4 base pairs.