Integrative Regulatory Mapping Indicates that the RNA-Binding Protein HuR Couples Pre-mRNA Processing and mRNA Stability
Open accessAbstract
RNA-binding proteins coordinate the fates of multiple RNAs, but the principles underlying these global interactions remain poorly understood. We elucidated regulatory mechanisms of the RNA-binding protein HuR, by integrating data from diverse high-throughput targeting technologies, specifically PAR-CLIP, RIP-chip, and whole-transcript expression profiling. The number of binding sites per transcript, degree of HuR association, and degree of HuR-dependent RNA stabilization were positively correlated. Pre-mRNA and mature mRNA containing both intronic and 3' UTR binding sites were more highly stabilized than transcripts with only 3' UTR or only intronic binding sites, suggesting that HuR couples pre-mRNA processing with mature mRNA stability. We also observed HuR-dependent splicing changes and substantial binding of HuR in polypyrimidine tracts of pre-mRNAs. Comparison of the spatial patterns surrounding HuR and miRNA binding sites provided functional evidence for HuR-dependent antagonism of proximal miRNA-mediated repression. We conclude that HuR coordinates gene expression outcomes at multiple interconnected steps of RNA processing.
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Hu binding sites are mostly located in 3′ UTRs of mRNAs, with a significant portion in introns and relatively few in 5′ UTRs.
“These studies also found that Hu binding sites were mostly located in 3′ UTRs of mRNAs, with a significant portion in introns and relatively few in 5′ UTRs.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Mukherjee et al. 2011
The Results section (HuR-RNA interactions and RNA Recognition Element, Figure 2A; page not available) reports 83,141 intronic binding-site clusters versus 22,353 in 3′ UTRs. Thus, although substantial 3′ UTR binding is reported, the claim that most sites are in 3′ UTRs is contrary to this paper's counts. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredHigh-throughput analyses of HuR and nELAV target mRNAs demonstrate that all four Hu proteins preferentially bind U-rich sequences interspersed with Gs or As.
“Recent high-throughput analyses, using variations of cross-linking and immunoprecipitation (CLIP) such as Photoactivatable-Ribonucleoside-Enhanced CLIP (PAR-CLIP) and individual-nucleotide resolution CLIP (iCLIP), of HuR and nELAV target mRNAs corroborate these findings by demonstrating that all four Hu proteins preferentially bind U-rich sequences interspersed with Gs or As (Lebedeva et al. 2011;”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Mukherjee et al. 2011
The Results section ('HuR-RNA interactions and RNA Recognition Element'; page unavailable) reports a PAR-CLIP analysis of HuR and identifies U-rich motifs interrupted by A or C. The Introduction describes uridine stretches separated by adenosines or, less commonly, other bases. This paper does not demonstrate the stated preference for Gs or As across all four Hu proteins; its high-throughput analysis examines HuR. (LLM, conf=0.87)
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- Authors
- Mukherjee, N., Corcoran, D. L., Nusbaum, J. D., Reid, D. W., Georgiev, S., Hafner, M., Ascano, M., Tuschl, T., Ohler, U., & Keene, J. D.
- Affiliations
- Duke Medical Center (US)
- Howard Hughes Medical Institute (US)
- Duke University (US)
- Corresponding author
- Keene, Jack D.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 43
- Issue
- 3
- Pages
- 327-339
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3220597
- OpenAlex
- W2059646461
- Cited by
- 654
- References
- 5
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 23 · 2023: 29 · 2022: 39 · 2021: 38 · 2020: 40 · 2019: 38 · 2018: 44 · 2017: 36 · 2016: 64 · 2015: 56 · 2014: 78 · 2013: 60 · 2012: 55
- FWCI
- 27.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Alnylam Pharmaceuticals
- Starr Foundation
- National Institutes of Health
- National Institute on Drug Abuse (DA030086, R01DA030086)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- HuR, RNA-binding proteins, mRNA stability, pre-mRNA processing, splicing, 3' UTR binding sites, polypyrimidine tract, microRNA binding sites, PAR-CLIP, RIP-Chip
- MeSH terms
- ELAV-Like Protein 1, Antigens, Surface, Binding Sites, Gene Expression Regulation, Humans, RNA Precursors, RNA Processing, Post-Transcriptional, RNA, Messenger, Software, RNA-Binding Proteins, Computational Biology, Amino Acid Motifs, RNA Stability, MicroRNAs, ELAV Proteins, HEK293 Cells
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