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

Abstract

N6-methyladenosine (m6A) 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 'm6A reader' proteins to fine-tune gene expression, such as mRNA degradation and translation initiation. Here we profiled transcriptome-wide m6A sites in adult mouse cerebral cortex, underscoring that m6A 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 m6A 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 m6A. Biochemical analyses indicate that FMRP binds to the m6A sites of its mRNA targets and interacts with m6A 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 m6A-marked mRNA targets through YTHDF2, which could potentially contribute to the molecular pathogenesis of FXS.

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

“…More importantly, focusing on FMRP's translational function in dendritic synapses overlooks the fact that the great majority of this protein is located in the cell soma 9 . Indeed, a wide range of research has associated FMRP to multiple steps of the mRNA life cycle, including pre-mRNA splicing 10 , mRNA editing 11,12 , miRNA activity 13,14 , and mRNA stability 15,16 . Additionally, FMRP may function outside the RNA-binding scope, by chromatin binding and regulating genome stability 17,18 , as well as directly binding to and regulating ion channels 19,20 .…”

The m6A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein

“…It would be of critical importance to test whether a similar mechanism also applies to mammals. The FMR1-mediated nuclear export and stability of methylated RNA as recently uncovered may contribute as well to the disease Hsu et al, 2019;Zhang et al, 2018). It is worth mentioning that while our study mainly focuses on two key Fmr1 targets involved in the gross morphology of the nervous system, it is likey that m 6 A and Fmr1 regulate additionnal targets involved in more subtle processes such as synapse functionality and complex trait behaviors.…”

N6-methyladenosine modification modulate in the heat stress of sheep (Ovis aries)

“…As a chemical marker, m 6 A has been identified in many animal and plant genes, and exerts effects in important biological pathways [49,50]. Zhou et al showed that HSP70 mRNA containing m 6 A modification sites in the 5 UTR underwent independent translation without depending on the N 7methylguanosine cap, while methylation was increased in the 5 UTR after HSP70 heat shock [20].…”