Press Release

26.03.2020

One for all, all for METTL(5)…

The novel and rapidly developing research field ‘Epitranscriptomics’ tackles one of the next challenges for modern biology: the mechanistic understanding of RNA modifications and their biological functions in health and diseases. Recently, the team of researchers lead by Robert Schneider (Institute of Functional Epigenetics, Helmholtz Zentrum München) have published the characterisation of a novel human RNA methyltransferase that is implicated in human diseases.

The central dogma of molecular biology describes the flow of hereditary information within living organisms, which was at first very straight forward: DNA makes RNA and RNA makes protein. However, over the last decades, research has demonstrated that the molecular mechanisms underlying gene expression are a lot more complex. The discovery of RNA modifications challenges again this long-standing relatively simple concept.

Small covalent modifications of RNA can regulate RNA function by affecting its localisation, stability or interaction with binding proteins. Thus far, over 170 RNA modifications have been identified on all types of RNAs. They are referred to as RNA “epi-modifications” and the corresponding research field as “epitranscriptomics”. Yet, the enzymatic machineries responsible for their deposition and their biological function are still under extensive investigation. One of such modification is methylation on an adenosine (A) (N6-methyladenosine (m6A)) in RNA. On human ribosomal RNAs (rRNAs) only two m6A-sites have been identified. They occur at positions within the ribosome, which are important for its function and might be implicated in human diseases such as ribosomapathies that accompany e.g. cancer development. Thus, the identification of novel RNA methyltransferases and their target sites is a high priority and will contribute to the design of selective inhibitors and potential therapies.

An international team of 31 researchers leaded by Helmholtz Zentrum Munich just published a study uncovering the molecular mechanisms that link rRNA methylation to development and disease. Ignatova et al. systematically screened proteins for methyltransferase activity on various types of RNAs. In doing so, Ignatova and colleagues have identified METTL5 as an RNA methyltransferase, that specifically methylates 18S rRNA at one site - close to the ribosome’s active centre. The team went ahead and showed that this modification plays an important role in translation, the process through which proteins are made in our cells. “A big step towards understanding the biological function of METTL5, was the characterisation of a Mettl5 knock out in mouse embryonic stem cells (mESCs). We thought it was important to ask whether rRNA modifications can regulate pluripotency and differentiation of stem cells,” said Valentina Ignatova, the first author of the project. She adds: “We were surprised by the clear phenotype we observed. The loss of METTL5 decreased the ‘pluripotency’ of stem cells and had a huge impact on their ability to differentiate towards neuronal lineages.”

An important milestone was the generation of a mouse model that lacks Mettl5 (Mettl5 KO) in collaboration with the German Mouse Clinic at the Helmholtz Zentrum München, one of the leading mouse clinics in systemic phenotyping of human disease models. The project team was then able to study the consequences of rRNA methylation in a full organism. They found that mice lacking METTL5 have impaired development, reduced weight and infertility. In particular, their altered behaviour and facial and anatomical malformations are rather extraordinary. This is truly exciting, because human patients with Mettl5 mutations exhibit also behavioural and anatomical abnormalities comparable to the phenotype observed in mice. Therefore, the Mettl5 KO mouse model will serve the community as a new disease model to study those neurological defects.

“We worked together with labs that have various unique expertise”, comments Valentina Ignatova. “This collaborative effort allowed us to perform a complete characterisation of a new RNA-modifying enzyme, reveal its molecular function and develop a new mouse model system for human diseases.”

The work of Ignatova et al. is published in Genes & Development. To read the full article, please go here.