AI Article Synopsis
- tRNAs undergo various modifications, including methylation, and mutations in the METTL1/WDR4 complex are linked to conditions like primordial dwarfism and brain malformations, but their functions in mammals remain unclear.
- Researchers developed advanced sequencing techniques to study mG tRNA methylation in mouse embryonic stem cells, identifying 22 modified tRNAs at a specific "RAGGU" motif.
- Findings indicate that the absence of METTL1 impacts ribosome function, affecting translation of genes related to the cell cycle and brain development and leads to issues in self-renewal and differentiation in stem cells.
Article Abstract
tRNAs are subject to numerous modifications, including methylation. Mutations in the human N-methylguanosine (mG) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and brain malformation, yet the molecular and cellular function in mammals is not well understood. We developed mG methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the mG tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian mG tRNA methylome and highlights its essential role in ESCs with links to human disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086580 | PMC |
| http://dx.doi.org/10.1016/j.molcel.2018.06.001 | DOI Listing |
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