Research
We use two approaches to investigate the connections between epigenetic gene regulation and evolution. First, we are carrying out in lab evolution experiments using the simple laboratory nematode Caenorhabditis elegans, to test the extent to which epigenetic differences between individuals can contribute to evolution in the absence of changes in DNA sequence. Second, we are investigating the evolution of a variety of epigenetic pathways, including small RNAs such as Piwi-interacting RNAs (piRNAs), DNA methylation and histone modification. To study this we are using comparative genomics across metazoan organisms to generate hypotheses that we test using C. elegans or in mammalian cells. This approach allows us to uncover potential reasons underlying changes in epigenetic regulation both between species and within cancer cells.
Transgenerational inheritance of epimutations
DNA is packaged as chromatin inside cell nuclei and may be in a loose open conformation, allowing expression of genes, or a tight closed conformation, preventing expression of genes. It is known that chromatin state can switch between closed and open states depending of environmental factors. Using the model organism C.elegans, we have shown that chromatin states can also mutate spontaneously under controlled conditions. By tracking chromatin states across generations of worms we have shown that mutated chromatin states can be inherited. We are now investigating to what extent this process might have on inherited gene expression patterns.
Evolutionary insights into off-target alkylation damage induced by DNMT activity
A well-understood epigenetic mechanism in eukaryotes is methylation at the 5 position of cytosine (5meC), predominantly at CpG dinucleotides. Although cytosine DNA methylation was ancestral to eukaryotes and is essential in many organisms, including mammals, it has been lost from several eukaryotic species. We have shown that DNA methylation co-evolves with the DNA alkylation repair gene AlkB2 in order to evade the toxicity caused by the DNMT-mediated off-target accumulation of 3-methylcytosine (3meC). We are now analysing this co-evolution more closely using E. coli as the model organism.
Extracellular miRNA in Trichinella spiralis
There is a growing interest in the potential role of extracellular miRNAs in novel cell-to-cell communication. Parasitic nematodes secrete a range of mediators, including small RNAs, to manipulate their host environment and therefore it is possible that extracellular miRNAs are also involved in parasite-to-host communication. We are using Trichinella spiralis as a model to study the biology of extracellular miRNA. We have shown that in the intramuscular stage they secrete unencapsulated miRNAs, which contrasts with the adult stage as well as with current descriptions of miRNA export within vesicles in various other systems. This raises questions over whether the unencapsulated miRNAs are secreted via direct release or in complex with a chaperone protein, which could offer protection in the absence of a membrane. We are therefore investigating the mechanism of secretion of miRNA in intramuscular T. spiralis.