An evolution of epigenetic mechanisms through genomic analyses of nematodes

The Department had the pleasure of hosting Peter Sarkies (Imperial College London) who gave a talk about his work concerning the evolution of epigenetic mechanisms through genomic analyses of the nematode phylum. Peter’s research has demonstrated how sampling organisms across a range of evolutionary distances within a single phylum, as opposed to being reliant on data from conventional model organisms that are evolutionarily very distant, can reveal fundamental molecular insights.

In the first part of his talk, Peter introduced his work on how animals have evolved robust machinery to silence transposons – mobile elements which if left unchecked can copy themselves independently of the host genome insert themselves into important coding genes. In most organisms, the first line of defence against transposons are small sequences of RNA, known as PIWI interacting small RNAs, (piRNAs), that seek out and control transposons.

However, Peter’s work showed that this broadly conserved transposon-silencing system has been lost in the nematode phylum on several occasions. Specifically, piRNAs have been lost in 4 out of 5 nematode clades, and only clade V, which contains the famous model organism Caenorhabditis elegans, uses the piRNA pathway. Worms lacking piRNAs have instead evolved two other pathways to combat transposons. One is a nematode-specific transposon silencing pathway known as 22G-RNAs, found in 3 clades. The other is an ancient pathway, dependent on RNA-directed DNA methylation, which is found in the oldest nematode clades (clades I and II). Interestingly, RNA-directed DNA methylation is also found in S. pombe and plants, leading to the possibility that it is most likely the ancestral mechanism for transposon silencing in animals.

In the second part of his talk, Peter described some recent unpublished findings regarding how methylation at position 5 of cytosine (5mec) can lead to DNA alkylation damage. 5meC in DNA is an important epigenetic mark in eukaryotes that is used to supress transcription, but its phylogenetic distribution is quite variable. Again, using samples from across the nematode phylum, Peter showed that although C elegans has lost DNA methylation, more basal nematodes have retained it to silence transposons.

Moreover, DNA methylation seems to have broadly coevolved with DNA repair in eukaryote evolution – including with a gene encoding for a DNA alkylation repair enzyme, ALKB2. Consequently, his group demonstrated that DNMTs cause alkylation damage in vitro and in vivo by introducing 3mec lesions into DNA. Thus, alkylation damage is a cost associated with DNA methyltransferase activity, which may drive loss of DNA methylation in many species. Interestingly, in many cancers DNA hypermethylation causes repression of critical growth regulators, and so ALKB2 inhibition may provide a promising therapeutic against cancer development.

It was enjoyable to hear from a speaker with a strong background in molecular biology (Max Perutz PhD prize from the LMB, post-doc from Gurdon Institute, Cambridge), but whose interest in evolutionary biology has informed his research questions with great success. We look forward to hearing more about his ‘Epi-Evo’ research over the next few years.  

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Paper on nematode piRNA loss: