m6A enhances the phase separation potential of mRNA

Binding to m6A RNA promotes YTHDF2-mediated phase separation

“…Interestingly, recombinant YTHDF2 protein containing the LC domain (YTHDF2 aa 230-383 ) forms liquid droplets (23 μM protein in 37 mM NaCl, 10% PEG8000), which are sensitive to 1,6-hexanediol (previously shown to specifically disrupt liquid-like assemblies) (Kroschwald et al,2017) (Figure 1B), suggesting phase separation. This phase separation ability is dependent on NaCl concentration (Supplementary Figure 1A), which is consistent with another report (Ries et al,2019). Moreover, we found these droplets fuse with each other to form bigger droplets, which further suggests a liquid like phase separation feature of YTHDF2 aa 230-383 (Supplementary Figure 1B, and supplementary Video 1).…”

Biomolecular condensates in neurodegeneration and cancer

“…Accordingly, RNA promotes or represses the phase separation of RNA‐binding proteins (depending on its concentration) and modulates the material properties of their condensates . RNA splicing, secondary structure and modifications have been shown to modulate cellular condensate assembly and composition . Similarly, various protein modifications have been shown to modulate condensate assembly (reviewed in Reference ), composition (reviewed in Reference ) and material properties .…”

m6A facilitates YTHDF‐independent phase separation

“…2 This phenomenon is similar to the mixing of water and oil or can be imagined as the process of raindrop formation over an umbrella on rainy days. 5 Recently, Ries et al 6 To address whether m 6 A regulates the phase separation of DF2 protein, the authors found that in m 6 A methyltransferase 14-knockout mouse embryonic stem cells, the formation of endogenous stress granules took place normally after exposure to heat shock; however, the localization of DF2 proteins in stress granules was significantly reduced. 3 Cells are separated from each other by phase separation to achieve a variety of biological functions.…”

“…Scientists progressively discovered that many cellular membrane-less organelles, such as nucleoli, Cajal bodies, stress granules, miRNA-induced silencing complex and synaptic cytoskeletons, are phase transitions of specific proteins. When cells are exposed to heat shock, the translation efficiency of modified m 6 demonstrated that an extensive amount of m 6 A-modified mRNA was localized to stress granules when cells were exposed to oxidative stress. As soon as LLPS behaves abnormally, disease onset may occur; however, what triggered the aggregation of some molecules but not others in the same droplet has never been elucidated.…”

“…4 The multivalent interaction of intracellular biological macromolecules is common and affected by some modifications, such as phosphorylation and methylation. 5 Recently, Ries et al 6 To address whether m 6 A regulates the phase separation of DF2 protein, the authors found that in m 6 A methyltransferase 14-knockout mouse embryonic stem cells, the formation of endogenous stress granules took place normally after exposure to heat shock; however, the localization of DF2 proteins in stress granules was significantly reduced. The localization of DF2 to stress granules under cellular stress is dependent on its modification with m 6 A.…”