RNA Methylation and Its Role in the Hematopoietic System

RNA methylation represents a novel expansion of traditional epigenetic concepts. RNAs can be methylated at adenine and at cytosine residues, and both modifications have distinct regulatory potential. Our work focuses on the DNMT2 enzyme, which is a member of the animal (cytosine-5) DNA methyltransferase family and has long been considered to function as a DNA methyltransferase. However, a DNA methyltransferase activity could not be confirmed conclusively and more recent work clearly demonstrates that DNMT2 is a tRNA methyltransferase. This unexpected substrate is interpreted to reflect an evolutionary ancient substrate switch from DNA to tRNA that expanded the epigenetic regulatory capacity of the DNMT family to also include RNA. To analyze the function of DNMT2, we performed a detailed analysis of knockout mice. These mice are viable and fertile, but also show a reduction of hematopoietic stem and progenitor cell populations and a cell-autonomous defect in their differentiation.¹ RNA bisulfite sequencing revealed that Dnmt2 methylates C38 of tRNA Asp(GTC), Gly(GCC), and Val(AAC). Proteomic analyses from primary bone marrow cells uncovered systematic differences in protein expression that are due to specific codon mistranslation by tRNAs lacking DNMT2-dependent methylation. Together, these results illustrate the regulatory capacity of DNMT2-mediated tRNA methylation in genome recoding.² Our current work addresses additional mechanistic aspects that link tRNA methylation to translational fidelity and investigates the relevance of DNMT2-mediated tRNA methylation for leukemogenesis.

1. Tuorto F, Herbst F, Alerasool N, et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 2015;34(18):2350-2362.

2. Tuorto F, Lyko F. Genome recoding by tRNA modifications. Open Biol. 2016;6(12):160287.