N(6)-methyladenosine-dependent RNA Structural Switches Regulate RNA-protein Interactions

Overview

Journal Nature

Specialty Science

Date 2015 Feb 27

PMID 25719671

Citations 1096

Authors

Nian Liu

Qing Dai

Guanqun Zheng

Chuan He

Marc Parisien

Tao Pan

Affiliations

Soon will be listed here.

Abstract

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. N(6)-methyladenosine (m(6)A), 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 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-structure-dependent accessibility of RBMs to affect RNA-protein interactions for biological regulation; we term this mechanism 'the m(6)A-switch'. We found that m(6)A 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-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 m(6)A-dependent RNA structural remodelling, and provide a new direction for investigating RNA-modification-coded cellular biology.

Citing Articles

METTL3-mA-mediated TGF-β signaling promotes Fuchs endothelial corneal dystrophy via regulating corneal endothelial-to-mesenchymal transition.

Qiu J, Zhang X, Shi Q, Yang Y, Zhou R, Xiang J Cell Death Discov. 2025; 11(1):104.

PMID: 40089501 DOI: 10.1038/s41420-025-02384-1.

NERD-dependent mA modification of the nascent FLC transcript regulates flowering time in Arabidopsis.

Shao Y, Ma J, Zhang S, Xu Y, Yu H Nat Plants. 2025; .

PMID: 40087542 DOI: 10.1038/s41477-025-01945-7.

The Role of MA Modification in Autoimmunity: Emerging Mechanisms and Therapeutic Implications.

Xu L, Shen T, Li Y, Wu X Clin Rev Allergy Immunol. 2025; 68(1):29.

PMID: 40085180 DOI: 10.1007/s12016-025-09041-6.

HNRNPC promotes progression of non-small cell lung cancer by maintaining TFAP2A mRNA stability.

Liao M, Li C, Yang R, Li J, Wu K, Zhang J Cancer Cell Int. 2025; 25(1):85.

PMID: 40057699 PMC: 11889907. DOI: 10.1186/s12935-025-03660-x.

Exon junction complexes regulate osteoclast-induced bone resorption by influencing the NFATc1 m6A distribution through the "shield effect".

Sun B, Yang J, Wang Z, Wang Z, Feng W, Li X Clin Transl Med. 2025; 15(3):e70266.

PMID: 40051055 PMC: 11885169. DOI: 10.1002/ctm2.70266.

References

Antson A . Single-stranded-RNA binding proteins. Curr Opin Struct Biol. 2000; 10(1):87-94. DOI: 10.1016/s0959-440x(99)00054-8. View

Zhao X, Yang Y, Sun B, Shi Y, Yang X, Xiao W . FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014; 24(12):1403-19. PMC: 4260349. DOI: 10.1038/cr.2014.151. View

Dreyfuss G, Kim V, Kataoka N . Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol. 2002; 3(3):195-205. DOI: 10.1038/nrm760. View

Kierzek E, Kierzek R . The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. Nucleic Acids Res. 2003; 31(15):4472-80. PMC: 169893. DOI: 10.1093/nar/gkg633. View

Ehresmann C, Baudin F, Mougel M, Romby P, Ebel J, Ehresmann B . Probing the structure of RNAs in solution. Nucleic Acids Res. 1987; 15(22):9109-28. PMC: 306456. DOI: 10.1093/nar/15.22.9109. View

Gorlach M, Burd C, Dreyfuss G . The determinants of RNA-binding specificity of the heterogeneous nuclear ribonucleoprotein C proteins. J Biol Chem. 1994; 269(37):23074-8. View

Peterson E, Pan T, Coleman J, Uhlenbeck O . In vitro selection of small RNAs that bind to Escherichia coli phenylalanyl-tRNA synthetase. J Mol Biol. 1994; 242(3):186-92. DOI: 10.1006/jmbi.1994.1571. View

Rajagopalan L, Westmark C, Jarzembowski J, Malter J . hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic Acids Res. 1998; 26(14):3418-23. PMC: 147701. DOI: 10.1093/nar/26.14.3418. View

Krecic A, Swanson M . hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol. 1999; 11(3):363-71. DOI: 10.1016/S0955-0674(99)80051-9. View

10.

Elemento O, Slonim N, Tavazoie S . A universal framework for regulatory element discovery across all genomes and data types. Mol Cell. 2007; 28(2):337-50. PMC: 2900317. DOI: 10.1016/j.molcel.2007.09.027. View

11.

Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z . GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009; 10:48. PMC: 2644678. DOI: 10.1186/1471-2105-10-48. View

12.

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

13.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

14.

Pollard K, Hubisz M, Rosenbloom K, Siepel A . Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2009; 20(1):110-21. PMC: 2798823. DOI: 10.1101/gr.097857.109. View

15.

Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P . Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell. 2010; 141(1):129-41. PMC: 2861495. DOI: 10.1016/j.cell.2010.03.009. View

16.

Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B . iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol. 2010; 17(7):909-15. PMC: 3000544. DOI: 10.1038/nsmb.1838. View

17.

Kertesz M, Wan Y, Mazor E, Rinn J, Nutter R, Chang H . Genome-wide measurement of RNA secondary structure in yeast. Nature. 2010; 467(7311):103-7. PMC: 3847670. DOI: 10.1038/nature09322. View

18.

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y . N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011; 7(12):885-7. PMC: 3218240. DOI: 10.1038/nchembio.687. View

19.

Corcoran D, Georgiev S, Mukherjee N, Gottwein E, Skalsky R, Keene J . PARalyzer: definition of RNA binding sites from PAR-CLIP short-read sequence data. Genome Biol. 2011; 12(8):R79. PMC: 3302668. DOI: 10.1186/gb-2011-12-8-r79. View

20.

Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley D . Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012; 7(3):562-78. PMC: 3334321. DOI: 10.1038/nprot.2012.016. View