N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions

By Nian Liu, Qing Dai, G. Zheng, Chuan He, Marc-André Parisien, T. Pan. Nature, 2015

1,493 citations recorded by the source corpus.

RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBMs). However, RBMs can be buried within their local RNA structures, thus inhibiting RNA–protein interactions. N6-methyladenosine (m6A), the most abundant and dynamic internal modification in eukaryotic messenger RNA, can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs, but how m6A achieves its wide-ranging physiological role needs further exploration. Here we show in human cells that m6A controls the RNA-structure-dependent accessibility of RBMs to affect RNA–protein interactions for biological regulation; we term this mechanism ‘the m6A-switch’. We found that m6A alters the local structure in mRNA and long non-coding RNA (lncRNA) to facilitate binding of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing. Combining photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m6A immunoprecipitation (MeRIP) approaches enabled us to identify 39,060 m6A-switches among HNRNPC-binding sites; and global m6A reduction decreased HNRNPC binding at 2,798 high-confidence m6A-switches. We determined that these m6A-switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m6A-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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8200a466d23fe0992632d0594c0e7b4d6a27de0c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Chuan He
2. Hailing Shi

In Molecular Biology

1. Chuan He
2. Syuzo Kaneko
3. Masaaki Komatsu
4. Ken Asada
5. Ken Takasawa
6. Hailing Shi
7. Jiangbo W
8. Amina Bolatkan

Citations in the corpus

• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “recently identified 39,060 m(6)A-switches among HNRNPC-binding sites and the majority (87%) of m(6)A-switches occur within introns.(11) Pendleton et al.”
• N 6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein (2017, methodology): “Previous results revealed thousands of RNA transcripts and hundreds of exons that are similarly up- or downregulated by HNRNPC knockdown and m6A methyltransferase knockdown (20).”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “Several heterogeneous nuclear ribonucleoproteins (HNRNPs) fall into this category, including HNRNPC, HNRNPG, and HNRNPA2B1, which regulate alternative splicing or processing of target transcripts (Alarcon et al., 2015a; Liu et al., 2015; Liu et al., 2017; Wu et al., 2018).”