N-6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions

Article

关键词: MESSENGER-RNA;    HNRNP C;    SECONDARY STRUCTURE;    NUCLEAR-RNA;    REVEALS;    TRANSCRIPTOME;    RESOLUTION;   

DOI  :  10.1038/nature14234

来源: SCIE

【 摘 要 】

RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBMs)(1-3). However, RBMs can be buried within their local RNA structures'', thus inhibiting RNA-protein interactions. N-6-methyladenosine (m(6)A), the most abundant and dynamic internal modification in eulcaryotic messenger RNA(8-19), can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs(15), but how m(6)A achieves its wide-ranging physiological role needs further exploration. Here we show in human cells that m(6)A controls the RNA-structuredependent accessibility of RBMs to affect RNA-protein interactions for biological regulation; we term this mechanism 'the m6A-switch'. We found that m(6)A alters the local structure in mRNA and long non-coding RNA (IncRNA) to facilitate binding of heterogeneous nuclear ribonudeoprotein C (HNRNPC), an abundant nuclear RNAbinding protein responsible for pre-mRNA processing'. Combining photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m(6)A immunoprecipitation (MeRIP) approaches enabled us to identify 39,060 m(6)A-switches among HNRNPC-binding sites; and global m(6)A reduction decreased HNRNPC binding at 2,798 high-confidence m(6)A-switches. We determined that these m(6)A-switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m(6)A-switches on gene expression and RNA maturation. Our results illustrate how RNA-binding proteins gain regulated access to their RBMs through m6A-dependent RNA structural remodelling, and provide a new direction for investigating RNA-modification-coded cellular biology.

【 授权许可】

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