5mC-mediated epigenetic inheritance in animals

Some sort of dogma about DNA methylation research posits that environmental changes might induce epigenetic changes, and these will be inherited in the next generation causing transcriptional adaptation. While this has been proposed many times, it has not been demonstrated conclusively. Most importantly, even if methylation states would be inheritable, their actual effect on transcription was unclear. At least in invertebrates, the role of gene body methylation was debated, but not well understood.

In an attempt to tackle this conundrum, we turned some years ago to a new model system in the lab, the sea anemone Nematostella vectensis. We chose it as it has a smallish well characterised genome, it is easy to rear, and experimental manipulation is possible. Also, it has canonical invertebrate gene body methylation patterns, which remain stable along development. By using a combination of DNMT1 disruption treatments, we obtained hypomethylated individuals, that could progress developmentally and even produce fertile gametes, all while keeping an hypomethylated state. By profiling transcription in these individuals, we found that a lot of the proposed models about gene body methylation are likely to be wrong, as we didn't see major effects on alternative splicing, disregulation of the methylated genes or unstable transcription. Instead, we found that spurious transcriptional start sites and regulatory elements emerged from the gene bodies that were previously methylated, many of these actually derived from Transposable Elements. This role is in fact consistent with what is known about gene body methylation in mammals, so it is probably the ancestral state for animal DNA methylation.

Because the hypomethylated individuals could produce gametes, we then looked at the inheritability of these aberrant methylation states. While DNA methylation came back to some degree in the germ line, fertilisation did not prompt any major wave of epigenetic reprogramming, and "epi-mutants" were passively inherited in the next generation. This story is now published in Nature Ecology and Evolution.

The starlet sea anemone, Nematostella vectensis. Picture taken by Karmannye Chaudhary from a lab specimen.

We think this is helpful for the field, as it confirms that variable DNA methylation can be transmitted across generations in animals, at least invertebrates. This is very similar to what is known for plants. However, it does not fit the simplistic "Lamarckian" narrative. Gene body methylation prevents Transposable Elements modulating gene expression, and the outcome of this is hard to predict, sometimes it might be beneficial for the host, perhaps not have much effect or even be detrimental. So the "environmental epigenetic adaptation" hypothesis so frequently proposed requires a revision. At least when talking about DNA methylation.