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Hum Mol Genet. 2018 Nov 15;27(22):3936-3950. doi: 10.1093/hmg/ddy292.

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

Author information

1
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
2
Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA, USA.
3
Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin, China.
4
Department of Neuroscience, Mahoney Institute for Neurosciences, Institute for Regenerative Medicine and The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5
The Children's Hospital and Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

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.

PMID:
30107516
PMCID:
PMC6216232
DOI:
10.1093/hmg/ddy292
[Indexed for MEDLINE]
Free PMC Article

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