Ribosome profiling on heat shocked wild type and Mettl14 -/- mES cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE109253 | GEO | 2021/01/15
REPOSITORIES: GEO
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Project description:N6-methyladenosine (m6A) is the most abundant nucleotide modification found on mRNA. m6A has been previously shown to facilitate recruitment of mRNAs to stress granules due to interactions between m6A and the YTHDF proteins. Although protein-RNA interactions are known to contribute to the recruitment of mRNAs to stress granules, the predominant driver of mRNA recruitment to stress granules is thought to be RNA-RNA interactions between long RNAs. Here, we show that m6A contributes significantly to the length-dependent effect of mRNA enrichment in stress granules and that upon depletion of METTL3, the enzyme responsible for adding m6A to nascent transcripts, the nature of the stress granule transcriptome is fundamentally altered by greatly reducing the propensity of long mRNAs to enter stress granules. This reveals that not only does m6A enhance the phase separation of mRNAs, but that it is a driving force underpinning length-dependent enrichment of mRNAs in stress granules.
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Project description:N6-methyladenosine (m6A) is the most abundant internal mRNA nucleotide modification in mammals, regulating critical aspects of cell physiology and differentiation. The YTHDF proteins are the primary readers of m6A modifications and exert physiological functions of m6A in the cytosol. Elucidating the regulatory mechanisms of YTHDF proteins is critical to understanding m6A biology. Here, we report a mechanism that protein post-translational modifications control the biological functions of the YTHDF proteins. We find that YTHDF1 and YTHDF3, but not YTHDF2, carry high levels of nutrient-sensing O-GlcNAc modifications. O-GlcNAc modification attenuates the translation promoting function of YTHDF1 and YTHDF3 by blocking their interactions with proteins associated with mRNA translation. We further demonstrate that O-GlcNAc modifications on YTHDF1 and YTHDF2 regulate the assembly, stability, and disassembly of stress granule, facilitating rapid exchange of m6A-modified mRNAs in stress granules for recovery from stress. Therefore, our results discover an important regulatory pathway of YTHDF functions, adding an additional layer of complexity to the post-transcriptional regulation function of mRNA m6A.
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