N6-methyladenosine-dependent RNA Structural Switches Modulate RNA-protein Interactions

Various chemical modifications have been found in cellular RNAs, but their functions remain an uncharted territory. N6 -methyladenosine (m6A), the most abundant and dynamic internal modification in eukaryotic messenger RNA (mRNAs), is indispensable for cell viability, pluripotency and human health, but how m6A achieves such wide-ranging biological functions remains unclear. The m 6A functional studies have been hindered by the lack of methods for its precise detection. To address this problem, I developed one method to detect m6A modification status at nucleotide-resolution, and identified exact m6A sites in human mRNAs and long non-coding RNAs (lncRNAs). Afterwards, I discovered that m6A alters the local RNA structure to control the RNA-structure-dependent accessibility of RNA binding sites, thus affecting RNA-protein interactions; I termed this mechanism 'm6A-switch'. Two members of heterogeneous nuclear ribonucleoproteins (HNRNPs), HNRNPC and HNRNPG, are found to be regulated by m6A-switches. These m6A-switch-regulated HNRNPC/G binding activities affect the RNA abundance and alternative splicing events. These findings illustrate how RNA-binding proteins gain regulated access to their RNA binding sites through m6A-dependent RNA structural remodeling, and provides a new direction for investigating RNA-modification-coded cellular biology.