The function of the RNA methylome in animals

Our DNA contains the core genetic information that is inherited by our children. This genetic information programs how and when genes will be expressed within the diverse number of cells of an organism. Epigenetic mechanisms such as chromatin and DNA modifications give rise to heritable gene expression changes without affecting the DNA code. Research in epigenetics led to the discoveries of novel gene regulatory mechanisms with heritable features. A similar paradigm has now emerged with RNA. RNA carries the message encoded in the DNA. Yet this message itself can also be altered by chemical modifications. There are currently more than 150 diverse modifications found on RNA and a greater number of proteins are required for their biogenesis and recognition. Recent discoveries have shown that RNA modifications can be dynamically regulated and they have been implicated in embryonic development, longevity, neurological diseases and cancers in humans and in animal models.

The heritable nature of epigenetic mechanisms requires gene expression changes within the germ cells, which give rise to the offspring. Germline development, germ cell proliferation and identity are essential for the survival of organisms. Epigenetic mechanisms play key roles in genome defence by targeting foreign elements and they also prevent somatic gene expression in the germ cells. Still, in some animals, it is possible to reprogram the epigenetic pathways to establish heritable gene expression changes that can last many generations.

The biological role of most RNA modifications remains unclear in multicellular organisms and their role in heritable gene expression regulation is not explored. Research using the nematode Caenorhabditis elegans as an animal model made pioneering contributions to the discovery and understanding of epigenetic gene regulatory pathways in animal germlines. Up until recently, the RNA modification landscape of C. elegans was not know. In order to establish C. elegans as a model system to study the role of RNA modifications, I developed mass spectrometry methods that enable the identification and quantification of modified RNAs. Using these methods, I showed that several RNA modifications found in C. elegans show changes upon stress such as dietary restriction or high temperatures. In some instances, these changes in RNA modifications can be reversed.

My research aims to uncover the role of a specific group of RNA modifications that contain a methyl group. By understanding how RNA methylations contribute to gene expression changes in germ cells, I aim to discover their epigenetic functions. Using a combination of biochemical and genetic methods, I will

(i) develop an enzyme specific sequencing method for methylated RNAs
(ii) study the role of RNA methylations in animal germ cells
(iii) investigate how RNA methylome itself is regulated by dietary metabolism

This research is important because, first the proposed sequencing method will benefit a large research community and enable the profiling of RNA methylations in multicellular organisms. Second, understanding the role of RNA modifications in germ cells will reveal their role in cell proliferation and differentiation that will benefit research in human diseases such as cancer and fertility. And finally, my research has the potential to pioneer a new research direction on how our diet can affect gene expression through RNA modifications.

Who will benefit from our research?

I will study the mechanisms of gene regulation by RNA modifications and the fundamental principles by which dietary metabolism can regulate RNA modification levels. My research direction will benefit academics studying gene regulatory mechanisms, developmental biology, epigenetics and metabolism by making direct contribution to knowledge and methodology in those fields. Furthermore, my research will develop tools and resources that would benefit non-academic research on therapeutic potential of RNA modifications. Research in epigenetics is featured by news outlets and popular science magazines at an increasing pace. This has generated a growing public interest in heritability of epigenetics. My research will benefit the public understanding of epigenetic mechanisms by providing a simple animal model system using C. elegans.

How will they benefit from our research?

Academic community: Open-access publications are essential for delivering research results to the widest academic audience. In the last 15 years, scientific publications have been transformed by online journals and repositories. I aim to publish my research results in reputable open-access journals. However, in today's science, open-access publications alone are not sufficient to reach maximum impact among the academic world. I aim to disseminate my research results ahead of publication, using pre-print repositories such as BiorXiv. Pre-print publications can drive important interactions and exchange of ideas relating to research which can lead to future collaborations. Furthermore, I will make all research data publically available in relevant databases (e.g. ENA, ProteinExchange, Wormbase) at the point of pre-print publications. I have personal experience in how immediate dissemination of research data can drive research in laboratories or in countries where access to such data is limited. Another emerging area of knowledge sharing is the research protocols. There are now a number of repositories where research protocols can be published such as the Nature Protocol Exchange. This leads important interactions with researchers and often to the improvement of research protocols that can save time and money.

Industry research: The therapeutics potential of RNA modifications have only been realized recently and the number of therapeutics companies in this area is constantly growing. My research on bioorthogonal labelling of RNA modifications has already gathered the support of an industry collaborator. Storm Therapeutics in Cambridge, UK is one of the few cancer therapeutics companies focusing on RNA modifications. My research will benefit therapeutics research in this area by delivering new methods for detecting modified RNAs. In addition, the engineering approach for RNA methyltransferases will generate knowledge that can be applied to mammalian systems and can guide future structural studies in drug discovery. Once I establish the bioorthogonal labelling approach, I plan to get in contact with companies engaged in developing RNA sequencing methods such as Illumina and Lexogen, in order to further explore the potential of this method.

Public communication and education: C. elegans is an ideal organism for communicating genetics to public with its visible phenotypes. I plan to increase the public impact of my research by participating in the annual Norwich Science Festival. I will use this opportunity to organise "citizen science" activities such as wild sampling of C. elegans. Furthermore, genome editing methods have become an important part of the biomedical research and industry. C. elegans is a very useful model system to introduce genome editing technologies to students as it can be demonstrated in relatively short time and at very low costs. I plan to host A-level students and degree students in the lab focusing on basic genome editing projects.