Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay. Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay

Maternal RNA degradation is critical for embryogenesis and is tightly controlled by maternal RNA-binding proteins. Fragile X mental-retardation protein (FMR1) binds target mRNAs to form ribonucleoprotein (RNP) complexes/granules that control various biological processes, including early embryogenesis. However, how FMR1 recognizes target mRNAs and how FMR1-RNP granule assembly/disassembly regulates FMR1-associated mRNAs remain elusive. Here we show that Drosophila FMR1 preferentially binds mRNAs containing m6A-marked “AGACU” motif with high affinity to contributes to maternal RNA degradation. The high-affinity binding largely depends on a hydrophobic network within FMR1 KH2 domain. Importantly, this binding greatly induces FMR1 granule condensation to efficiently recruit unmodified mRNAs. The degradation of maternal mRNAs then causes granule de-condensation, allowing normal embryogenesis. Our findings reveal that sequence-specific mRNAs instruct FMR1-RNP granules to undergo a dynamic phase-switch, thus contributes to maternal mRNA decay. This mechanism may represent a general principle that regulated RNP-granules control RNA processing and normal development. Overall design: RNA-seq of embryos at the indicated stages were generated by deep sequencing, in duplicate, using NovaSeq platform. MeRIP-Seq of embryos at the indicated stages were generated by deep sequencing, in duplicate, using illumina Hiseq instrument.