An international team of researchers lead by Helmholtz Zentrum München uncovered the molecular mechanisms that link rRNA methylation to development and disease. The study was published “Genes & Development”.
Almost all cellular RNAs are covalently modified and these modifications have emerged as a crucial layer in the regulation of RNA biogenesis and functions. The mechanistic understanding how these modifications are catalyzed by enzymes is not well explored. Due to the potential implications of RNA methyltransferases in human health, the characterization of novel enzymes and their function could not only uncover new mechanisms, but also novel targets for the development of selective inhibitors and therapies. rRNA modifications have been associated with altered translation in different diseases, such as cancer and infectious diseases before.
The scientists involved in this study screened the METTL protein family members for RNA methyltransferase activity and showed that METTL5 is a novel m6A-methyltransferase that methylates S rRNA. Further, they could show that METTL5 is required for efficient translation and has a profound impact on cell function and pluripotency. Interestingly, the characterization of mouse embryonic stem cells revealed, that the loss of Mettl5 decreases the pluripotency of stem cells and impairs their ability to differentiate towards neuronal lineages.
As a next step, the German Mouse Clinic generated a Mettl5 KO mouse model and performed systemic phenotyping of all clinical relevant organs. The results support the importance of METTL5 for development. Mettl5 KO mice were subviable and had multiple developmental and behavioral phenotypes. The weight of homozygote Mettl5 KO mice was significantly reduced and microcomputed tomography and X-ray imaging revealed visible craniofacial abnormalities in about a half of the Mettl5 KO mice of both sexes. Image analyses demonstrated snout deviation due to altered nasal bone development and incomplete fusion of the frontal bone suture. In the KO mice, hearing thresholds were increased and the eyes presented abnormal retrolental tissue composed of melanocytes and endothelial cells. The eye phenotype appeared asymmetrically, with prevalence in the right eye. In an open field behavioral test that assesses spontaneous locomotor activity in a novel environment, Mettl5 KO mice were hypo-active and hypo-exploratory. In line with the impaired differentiation potential observed in Mettl5 KO embryonic stem cells, these results highlight an important role of METTL5 in mouse development.
Strikingly, the loss of the m6A methyltransferase METTL5 in mice reflects behavioral phenotypes and malformations of the skull also observed in human patients with METTL5 linked mutations. DNA variants associated with METTL5 have been reported in human patients with learning impairment, intellectual disorders, motor-weakness, microcephaly, and nasal bone deformation. Investigating the Mettl5 KO mouse model further can shed light on the underlying mechanisms of these defects and may lead to the development of potential therapies.
Valentina V. Ignatova, Paul Stolz, Steffen Kaiser, Tobias H. Gustafsson, Palma Rico Lastres, Adrián Sanz-Moreno, Yi-Li Cho, Oana V. Amarie, Antonio Aguilar-Pimentel, Tanja Klein-Rodewald, Julia Calzada-Wack, Lore Becker, Susan Marschall, Markus Kraiger, Lillian Garrett, Claudia Seisenberger, Sabine M. Hölter, Kayla Borland, Erik Van De Logt, Pascal W.T.C. Jansen, Marijke P. Baltissen, Magdalena Valenta, Michiel Vermeulen, Wolfgang Wurst, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Oliver J. Rando, Stefanie M. Kellner, Sebastian Bultmann, and Robert Schneider.
The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs. Genes Dev. 2020;34(9-10):715-729. doi:10.1101/gad.333369.119