N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions
Open accessAbstract
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.
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HNRNPA2B1 and HNRNPC exhibit selective binding to mRNAs containing m6A.
“According to a previous study, the HNRNP proteins HNRNPA2B1 and HNRNPC exhibit selective binding to mRNAs containing m6A.364,365”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [365]
The paper’s Abstract (page not supplied) reports that m6A-dependent RNA structural changes enhance hnRNP C binding to target transcripts, including mRNAs. The passages found do not establish the same claim for HNRNPA2B1, so the statement about both proteins is only partly supported by this source. (LLM, conf=0.88)
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- Authors
- Liu, N., Dai, Q., Zheng, G., He, C., Parisien, M., & Pan, T.
- Affiliations
- University of Chicago (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Parisien, Marc
- Pan, Tao
- Venue
- Nature
- Published
- 2015-02-25
- Volume
- 518
- Issue
- 7540
- Pages
- 560-564
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4355918
- OpenAlex
- W1981629946
- Cited by
- 1,988
- References
- 8
- Citations by year
- 2026: 127 · 2025: 188 · 2024: 222 · 2023: 238 · 2022: 248 · 2021: 305 · 2020: 203 · 2019: 120 · 2018: 131 · 2017: 99 · 2016: 67 · 2015: 39 · 2014: 1
- FWCI
- 48.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR000430)
- National Human Genome Research Institute (K01HG006699)
- National Institute of General Medical Sciences (R01GM088599, GM088599)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- N6-methyladenosine, RNA modification, RNA-binding proteins, RNA-protein interactions, RNA structure, HNRNPC, long non-coding RNA, mRNA structure, pre-mRNA processing, YTHDF2, PAR-CLIP, MeRIP-seq
- MeSH terms
- Adenosine, Base Sequence, Cross-Linking Reagents, HeLa Cells, Humans, Nucleic Acid Conformation, Protein Binding, RNA, Messenger, Alternative Splicing, Heterogeneous-Nuclear Ribonucleoprotein Group C, Immunoprecipitation, HEK293 Cells, Nucleotide Motifs, Transcriptome
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