Transcriptome-wide Analysis of Regulatory Interactions of the RNA-Binding Protein HuR
Open accessAbstract
Posttranscriptional gene regulation relies on hundreds of RNA binding proteins (RBPs) but the function of most RBPs is unknown. The human RBP HuR/ELAVL1 is a conserved mRNA stability regulator. We used PAR-CLIP, a recently developed method based on RNA-protein crosslinking, to identify transcriptome-wide ∼26,000 HuR binding sites. These sites were on average highly conserved, enriched for HuR binding motifs and mainly located in 3' untranslated regions. Surprisingly, many sites were intronic, implicating HuR in mRNA processing. Upon HuR knockdown, mRNA levels and protein synthesis of thousands of target genes were downregulated, validating functionality. HuR and miRNA binding sites tended to reside nearby but generally did not overlap. Additionally, HuR knockdown triggered strong and specific upregulation of miR-7. In summary, we identified thousands of direct and functional HuR targets, found a human miRNA controlled by HuR, and propose a role for HuR in splicing.
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High-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 Lebedeva et al. 2011
The section “PAR-CLIP reproducibly recovers in vitro HuR motifs” reports abundant HuR-binding motifs that are U-rich, including sequences containing A or G. The Introduction says HuB, HuC and HuD bind U-rich elements, but this paper’s high-throughput motif analysis is of HuR; it does not demonstrate the stated G- or A-interspersed preference for all four Hu proteins. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHu 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 Lebedeva et al. 2011
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- Authors
- Lebedeva, S., Jens, M., Theil, K., Schwanhäusser, B., Selbach, M., Landthaler, M., & Rajewsky, N.
- Affiliations
- Max Delbrück Center (DE)
- Corresponding author
- Rajewsky, Nikolaus
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 43
- Issue
- 3
- Pages
- 340-352
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2050108172
- Cited by
- 716
- References
- 14
- Citations by year
- 2026: 26 · 2025: 27 · 2024: 36 · 2023: 28 · 2022: 37 · 2021: 60 · 2020: 50 · 2019: 45 · 2018: 58 · 2017: 47 · 2016: 52 · 2015: 56 · 2014: 74 · 2013: 56 · 2012: 48
- FWCI
- 23.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- 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, post-transcriptional regulation, PAR-CLIP, 3' untranslated region, microRNA binding sites, miR-7, splicing
- MeSH terms
- ELAV-Like Protein 1, Animals, Antigens, Surface, Base Sequence, Binding Sites, Gene Expression Regulation, HeLa Cells, Humans, Reproducibility of Results, RNA-Binding Proteins, Conserved Sequence, Alternative Splicing, Sequence Analysis, RNA, Gene Expression Profiling, RNA Splice Sites, Immunoprecipitation, ELAV Proteins
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