RNA Epigenetics

Over 100 types of RNA modifications have been reported on different classes of RNA (modomics.genesilico.pl). Their functions have been, so far, mostly studied on highly abundant RNA such as transfer and ribosomal RNA. However, in the last few years, due to the advance of technological development, it has become clear that several RNA modifications are present on messenger RNA (Figure 1) and they can play critical role in post-transcriptional gene regulation.

Figure 1: Some modifications found on mRNA

Similar to epigenetic marks on the DNA, these modifications are often highly conserved and can be dynamically regulated upon environmental changes. Importantly, their misregulation has been associated with various kinds of developmental defects and diseases, such as obesity, neuronal disorders and cancers. Altogether, recent studies revealed an entirely new layer of gene expression regulation, which has been central to the development of a novel concept called “RNA epigenetics or epitranscriptomics”. However, the exact biological function of the majority of modified RNA nucleotides remains to be discovered.

Figure 2. Schematic representation of the m6A methyltransferase complex. Names of the components are indicated for mouse and Drosophila proteins

Insights into the m6A mRNA pathway

Using molecular biology and classical genetic approaches combined with high throughput techniques and computational tools, our lab study the contribution of mRNA modifications in the regulation of cell fate. Our pioneering investigations on the m6A RNA modification in Drosophila revealed its abundance and its critical role in neurogenesis and sex determination. We also identified several new players of the m6A methyltransferase complex, which are conserved from fly to human (Figure 2). To further characterizing this modification, we are developing novel approaches to profile m6A in vivo, in different population of cells. Furthermore, we are further investigating the molecular function of different components of the m6A pathway as well as the mechanisms underlying their regulation.

Characterising novel mRNA modifications

In close collaboration with chemists and computational biologists who are developing tools to map RNA modifications, we are investigating the molecular and functional role of novel mRNA modifications during cell differentiation and diseases. To this end, we are using genetic models (Drosophila and mammalian cell culture) to manipulate writers, erasers and readers of these modifications. One of our goals is to obtain a comprehensive view of their distributions and functions in order to identify potential interplay among them. In addition, we are studying their global effect on gene regulation, including their connection with other processes such as transcription, mRNA processing and translation.

Outlook

Our future work aims at further dissecting the m6A mRNA pathway to identify critical factors involved in m6A deposition (writer complex), removal (erasers) and recognition (readers), in different cellular contexts. Similar studies will be employed to characterise novel mRNA modifications. Ultimately, our study strives to expose a novel layer of gene regulation and unlock a previously hidden epitranscriptomics code.

Jean-Yves is an Associate Member of the EpiGeneSys network of scientists.

Interested PhD students, postdocs or Master's students are encouraged to apply.