Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain
Open accessAbstract
Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing.
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ELAVL4 regulates RNA splicing.
“ELAVL4 regulates RNA splicing (Scheckel et al., 2016)”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Scheckel et al., 2016
The Results section, “nELAVL regulates splicing of human brain targets” (page unavailable), reports altered exon splicing after nELAVL depletion. But the depletion targeted ELAVL2, ELAVL3, and ELAVL4 together, as specified in “nELAVL proteins regulate mRNA abundance of human brain targets” (page unavailable). The paper therefore supports a role for the neuronal ELAVL proteins in splicing, not an independently established role for ELAVL4 alone. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPublished nELAVL CLIP-seq data from human brain found that hCACNA1C, hCACNA1E and hCACNA1I are targets of nELAVL proteins.
“a published nELAVL CLIP-seq experiment from human brain found that hCACNA1C, hCACNA1E and hCACNA1I are targets of nELAVL proteins66”
From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [66]
The Results section, “Identification of nELAVL targets in human brain” (page unavailable), confirms that the authors performed CLIP on human brain samples and identified nELAVL RNA-binding sites. The passages in our copy do not identify CACNA1C, CACNA1E, or CACNA1I as targets; searches for those gene names found no matching passage. Thus the experiment is supported, but the specific target list is not verified. (LLM, conf=0.82)
Experimental — accuracy not yet measured
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“We generated a map from intronic nELAVL binding sites that flanked the 155 nELAVL regulated exons as previously described (Licatalosi et al., 2008), revealing that upstream nELAVL binding can promote both exon inclusion and skipping (Figure 4D).”
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- Authors
- Scheckel, C., Drapeau, E., Frias, M. A., Park, C. Y., Fak, J., Zucker-Scharff, I., Kou, Y., Haroutunian, V., Ma'ayan, A., Buxbaum, J. D., & Darnell, R. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
- James J. Peters VA Medical Center (US)
- Department of Pharmacology and Systems Therapeutics, BD2K-LINCS Data Integration and Coordination Center, Mount Sinai Knowledge Management Center for Illuminating the Druggable Genome, Icahn School of Medicine at Mount Sinai, New York, United States
- Corresponding author
- Buxbaum, Joseph D
- Darnell, Robert B
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-02-19
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4798961
- OpenAlex
- W2296696778
- Cited by
- 139
- References
- 15
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 10 · 2023: 12 · 2022: 15 · 2021: 22 · 2020: 22 · 2019: 11 · 2018: 16 · 2017: 9 · 2016: 6
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- EMBO (Long-Term Fellowship)
- SNF (Early and Advanced Postdoc Mobility Fellowship)
- Seaver Foundation (Graduate Fellowship)
- National Institutes of Health (ADRC AG005138, AG02219, HHSN27120130031C, R01GM098316, U54CA189201, U54HL127624, NS081706, NS34389)
- G Harold and Leila Y. Mathers Foundation
- Simons Foundation
- Howard Hughes Medical Institute
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- RNA-binding proteins, RNA splicing regulation, Alzheimer's disease, differential splicing, 3' UTR binding, UV stress, neuroblastoma cells, human brain transcriptome, RNA-protein interactions
- MeSH terms
- Alzheimer Disease, Animals, Brain, Gene Expression Regulation, Humans, Neurons, Protein Binding, RNA Splicing, RNA, Messenger, Mice, Knockout, RNA, Untranslated, RNA Interference, Cell Line, Tumor, ELAV Proteins
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