Multivalent m⁶A motifs promote phase separation of YTHDF proteins

Dear Editor,

The molecular mechanism by which these YTHDF1/2/3 proteins carry out their functions is largely unknown. It is also unclear whether the phase separation properties of the proteins contribute to their functions and, if so, how they are regulated. Recent studies using nucleotide-resolution sequencing techniques in human or mouse cell lines identified tens of thousands of m⁶A modification sites,^10,11 which preferentially localize around the stop codons or the beginning of the last exon of mRNAs.^5,11 For instance, 19 and 17 m⁶A modification sites are detected within an 820-bp and a 1040-bp region of EEF2 mRNA and JUN mRNA, respectively (Fig. S4). Some long noncoding RNAs also contain clusters of m⁶A modification sites. For example, 19 m⁶A modification sites are detected within an 820-bp region of XIST (Fig. S4). In a polyA-containing dataset published by Jaffery and colleagues,¹² we identified nearly 200 m⁶A clusters (Table S1), which, by definition, contain at least 5 m⁶A sites. These observations led us to wonder whether multiple co-existing m⁶A motifs can promote phase separation of YTHDFs by simultaneously binding multiple copies of YTHDF proteins.

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