How a complex, multicellular organism develops from a single fertilised egg is among the most intriguing concepts in biology. This phenomenon is further augmented by the fact that metazoan organisms consist of many distinct cell types that largely differ in their morphology, function and gene expression patterns, yet contain identical genomic DNA. Nowadays, we know that such a vast variety of cell types is generated and maintained by mechanisms that in most cases do not involve alterations in the primary DNA sequence. Such epigenetic mechanisms include (but are not limited to): DNA methylation, post-translational modifications of histone tails, long non-coding RNA and nucleosome positioning. The development of massively parallel DNA sequencing technologies has facilitated the generation of precise epigenome maps corresponding to myriad cell-lines, tissues and disease samples with the aim of deciphering the epigenomic component of diverse cellular forms and functions.
The research in our lab aims to understand the contributions of the epigenome to embryonic development, cell differentiation and disease. We are particularly interested in how DNA methylation patterns are established, maintained and altered during those processes. Our interest in DNA methylation stems from the fact that this epigenetic mark can be stably propagated through cell division and that the presence or absence of DNA methylation correlates well with the activity of regulatory regions. Finally, a vast wealth of studies has demonstrated strong links between DNA methylation and various disease phenotypes suggestive of its potential applicability as a biomarker.
Non-canonical DNA methylation as a regulator of embryonic genome function
We have recently described embryonic reprogramming of non-canonical DNA methylation (mCH, where H = C, T, A) within mosaic satellite repeats (MOSAT mCH), coincident with zygotic genome activation (Ross et al, 2020; Nuc Acids Res). Our CRISPR/Cas9 functional analyses in zebrafish larvae have unravelled Dnmt3ba as the primary MOSAT mCH methyltransferase enzyme. By using CRISPR/Cas9 and Cas13d genome editing technology in zebrafish, we are functionally interrogating the contribution of mCH and Dnmt3ba to embryogenesis, to better understand the developmental requirements for proper mCH patterning.
The rogue germline: epigenetic regulation of cancer testis antigens in embryonic development and cancer
A surprisingly small number of genes becomes silenced by promoter DNA hypermethyation during vertebrate embryogenesis. In many cases, these genes are essential regulators of germline development that are frequently found altered in multiple adult cancers. Through a combination of biochemical and zebrafish transgenesis approaches we are trying to understand the mechanisms of this targeting specificity as well as the roles of these genes in embryonic development cancer formation in vivo.
Bluebottle blues: System level characterisation of the siphonophore, Indo-Pacific man o’ war (bluebottle)
The overarching objective of this project is to utilise system level approaches and functional analysis to establish foundation knowledge of the Indo-Pacific man o’ war (bluebottle), a marine animal that is infamous for their painful sting. Bluebottles are not jellyfish, yet are siphonophores, a remarkable group of animals that are made up of colonies of highly modified individuals (zooids). This makes them an exciting species to study at the genome, epigenome and proteome levels to further our understanding of animal multicellularity and toxins.