Uncovering the properties and hidden secrets of ribonucleic acid (RNA) has been fundamental to advancing biomedical research and has become even more important with the emergence of COVID-19, one of the most contagious RNA viruses ever encountered.

Recently, a specific type of RNA, called messenger ribonucleic acid (mRNA), has featured heavily in news reports because it forms the basis of two leading COVID-19 vaccine candidates.

But Professor Thomas Preiss, a group leader at the John Curtin School of Medical Research (JCSMR), has been interested in mRNA long before it hit the headlines as part of a global pandemic.

mRNA plays a vital role in human biology, specifically in the protein synthesis process. It is a copy of a genetic sequence that instructs how to make proteins in our cells.

Professor Preiss was responsible for publishing chemical modification maps of mRNA that are now a critical part of the field of epitranscriptomics. Research since the release of these maps indicates the biological importance of the epitranscriptome may rival the epigenome.

Now, Professor Preiss and his colleagues, Dr Rippei Hayashi and Professor Eduardo Eyras, have been awarded an Australian Research Council (ARC) Discovery Project Grant to further investigate mRNA and its chemical modifications.

For a long time, it was thought that the chemical modifications of the genome (epigenome) were the only way to achieve multiple functions from the same nucleotide sequence, and that mRNAs were mere messengers of the genetic information.

“We now know that our cells use similar mechanisms of writing, reading, and erasing modifications in mRNAs. This is essential to describe the normal function of cells and is implicated in vaccine design and efficacy” said Professor Preiss.

“In this project, we aim to identify, map and understand the functionality of chemical modifications on mRNA that are currently not well understood.”

“Put simply, we need to know what is there, and what it is there for.”

“mRNA vaccines are already based on chemically decorated mRNA. But at present these decorations are placed based on empirical data as to how well cells react to the vaccine. Future developments could be based on mimicking the actual epitranscriptomic code that cells use.

“This could expand both, the efficiency and the range of applications of mRNA therapeutics, including improving vaccine design.”

In a search for knowledge this project brings together three key areas of biology, fly genetics, RNA biochemistry and bioinformatics, and is a joint collaboration between Professor Thomas Preiss, Professor Eduardo Eyras and Dr Rippei Hayashi.

Pioneering the field of epitranscriptomics

Our DNA is chemically modified, or decorated, to determine which parts of our genes are active or silent. This results in changes in the expression of our genes that do not alter the underlying structure of our DNA and is called epigenetics.

Precise epigenome changes are required to build and sustain complex life.

Epigenetics determines our different cell types during development. All living cells need to selectively retrieve information from genes in response to a changing environment. They do this by transcribing the necessary information from DNA into RNA molecules.

“If DNA is a complete recipe book, the messenger RNA (mRNA) is a copy of a particular recipe that instructs a specific cell what to make on a day-to-day basis” explains Professor Preiss.

In contrast to DNA, mRNA transcripts were thought to be mostly devoid of chemical modifications until 2012, when Professor Preiss released the first transcriptome-wide map of chemically modified mRNA.

Since 2012, the study of chemically modified RNA has come to be known as the field of epitranscriptomics and has developed extensively, but we still don’t have a good understanding of the location or function of these mRNA decorations. 

These mRNA decorations may provide an intermediate layer of instructions to the cell of how these messengers are processed, transported and translated into functional proteins.

Curiosity driven collaboration

The intended outcomes of the Discovery Projects scheme are to expand the knowledge base and research capacity in Australia. Professor Preiss is proud of this investment in basic science from the ARC, saying “we hope to feed the research community in Australia with new discoveries.”

“Of course, the translational aspects of discovery science aren’t always immediately obvious, because you can’t know what you might do with knowledge until you have it.”

“But in this case, we know that further understanding of mRNA will inform the development of a variety of therapeutics.”

“We are relying on each other’s expertise for this project’s success” he continues, referring to the expertise of the study co-leads Professor Eyras and Dr Hayashi.

This project uses cutting edge technology that delivers long-read sequence data in real-time available in the Biomolecular Resource Facility at JCSMR.

“Long-read sequencing techniques opened up possibilities to address basic questions in molecular biology that we couldn't answer before, by allowing the direct reading of biochemical modifications in individual nucleic acid molecules” said JCSMR group leader Dr Hayashi.

Dr Hayashi’s research combines cutting-edge biochemical approaches and next-generation sequencing techniques in the fruit fly model organism, which is critical in understanding the function of mRNA decorations.

“This new technology allows us to study genomes and transcriptomes at unprecedented depth” said Professor Eduardo Eyras, EMBL Australia group leader and expert in computational RNA biology.

“This is a new frontier in understanding gene expression and will pave the way for assessing the impact of epitranscriptomic marks in normal cell function and disease.”