Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets

N-6-methyladenosine (m(6)A) is the most prevalent internal modification of mammalian messenger RNAs (mRNAs) and long non-coding RNAs. The biological functions of this reversible RNA modification can be interpreted by cytoplasmic and nuclear 'm(6)A reader' proteins to fine-tune gene expression, such as mRNA degradation and translation initiation. Here we profiled transcriptome-wide m(6)A sites in adult mouse cerebral cortex, underscoring that m(6)A is a widespread epitranscriptomic modification in brain. Interestingly, the mRNA targets of fragile X mental retardation protein (FMRP), a selective RNA-binding protein, are enriched for m(6)A marks. Loss of functional FMRP leads to Fragile X syndrome (FXS), the most common inherited form of intellectual disability. Transcriptome-wide gene expression profiling identified 2035 genes differentially expressed in the absence of FMRP in cortex, and 92.5% of 174 downregulated FMRP targets are marked by m(6)A. Biochemical analyses indicate that FMRP binds to the m(6)A sites of its mRNA targets and interacts with m(6)A reader YTHDF2 in an RNA-independent manner. FMRP maintains the stability of its mRNA targets while YTHDF2 promotes the degradation of these mRNAs. These data together suggest that FMRP regulates the stability of its m(6)A-marked mRNA targets through YTHDF2, which could potentially contribute to the molecular pathogenesis of FXS.