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HITS-CLIP yields genome-wide insights into brain alternative RNA processing
Open accessAbstract
Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA-binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3' untranslated regions, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.
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“crosslinking and immunoprecipitation followed by high-throughput sequencing (HITS-CLIP) has been developed to isolate RNA fragments directly bound by an RBP of interest (Darnell, 2010; Licatalosi et al., 2008; Moore et al., 2014; Ule et al., 2005a).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Licatalosi et al., 2008
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“Indeed, dual functions for splicing regulators in 3′-end poly-A site selection and mRNA transport have been described26,27”
From A compendium of RNA-binding motifs for decoding gene regulation (2013) · cites this paper as [26]
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“Alternative splicing (AS) is a highly tissue-specific process18 that greatly increases the complexity of the potential set of RNA molecules produced from multi-exon genes.”
From Decoding neuroproteomics: integrating the genome, translatome and functional anatomy (2014) · cites this paper as [18]
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InfluentialTranscriptome-wide Analysis of Regulatory Interactions of the RNA-Binding Protein HuR
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“However, splicing regulators can often affect alternative splicing in a position-dependent manner, as has recently emerged from genomewide analysis of RNA-binding splicing regulators (Licatalosi et al., 2008; Yeo et al., 2009).”
InfluentialUnderstanding the transcriptome through RNA structure
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“Accordingly, many splicing factors apart from hnRNP C are recruited to specific sets of polypyrimidine tracts to regulate downstream exons (Licatalosi et al., 2008; Llorian et al., 2010; Wang et al., 2012; Xue et al., 2009), and some of these were shown to modulate U2AF65 binding.”
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Bartoniček, N., Mååg, J. L. V., & Dinger, M. E. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0530-6 · Cited by 464
“The specificity of RIP has been improved in by UV crosslinking of RNA and protein in Cross-Linking ImmunoPrecipitation (CLIP) [143] and the later modifications with sequencing (HITS-CLIP) [144] and iClip [145].”
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“The advent of deep sequencing, coupled with new methods to isolate RNAprotein complexes, is facilitating a new depth of understanding about the RNA species in a cell and how proteins control splicing, transport, translation, and the subcellular location of these species (Licatalosi et al., 2008).”
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“…in the control of large networks of alternative exons, splicing regulators such as Nova and hnRNP H1 function in the regulation of alternative polyadenylation (APA) through direct binding to recognition sites clustered around the CPA signals (Katz et al., 2010; Licatalosi et al., 2008) (Figure 4B).”
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“on 9 Alternative Splicing scribed by Licatalosi et al. (2008) with minor modifications (see Supplemental ein (y axis) is represented relative to the position of alternative cassette exons (x axis).”
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“The main differences between our regulatory maps and previous ones (Huelga et al., 2012; Licatalosi et al., 2008; Pandit et al., 2013) are that: (1) our model reports probabilities, rather than density units, because they are more intuitive; (2) whereas previous studies report background models as…”
InfluentialAn ESRP‐regulated splicing programme is abrogated during the epithelial–mesenchymal transition
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“Several high-throughput methods for mapping binding sites of RNA-binding proteins based on crosslinking and immunoprecipitation (CLIP) were recently introduced (Hafner et al., 2010; König et al., 2010; Licatalosi et al., 2008; Ule et al., 2005).”
MethodInfluentialLong noncoding RNAs: fresh perspectives into the RNA world
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Background“Cotranscriptionality”: The Transcription Elongation Complex as a Nexus for Nuclear Transactions
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“Alternative poly(A) site choice has recently been recognized as a widespread phenomenon that shapes the repertoire of 30UTR sequences (Licatalosi et al., 2008; Sandberg et al., 2008) and is perturbed in cancer cells (Mayr and Bartel, 2009).”
Metadata
- Authors
- Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., Darnell, J. C., & Darnell, R. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- MRC Laboratory of Molecular Biology (GB)
- Affymetrix (United States) (US)
- Rockefeller University (US)
- Corresponding author
- Darnell, Robert B.
- ORCID
- Venue
- Nature
- Published
- 2008-11
- Volume
- 456
- Issue
- 7221
- Pages
- 464-469
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2597294
- OpenAlex
- W2044117548
- Cited by
- 1,352
- References
- 51
- Citations by year
- 2026: 37 · 2025: 53 · 2024: 46 · 2023: 44 · 2022: 72 · 2021: 81 · 2020: 59 · 2019: 77 · 2018: 85 · 2017: 89 · 2016: 95 · 2015: 97 · 2014: 103 · 2013: 89 · 2012: 111
- FWCI
- 29.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke (R01NS040955, R01 NS34389, R01NS034389)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD040647)
- 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
- HITS-CLIP, RNA-protein interactions, alternative splicing, nova, alternative polyadenylation, 3' untranslated region, RNA binding sites, brain, neurons, splicing factors, genome-wide mapping
- MeSH terms
- Neuro-Oncological Ventral Antigen, Animals, Antigens, Neoplasm, Cell Line, Cross-Linking Reagents, Exons, Humans, Neurons, Organ Specificity, RNA, Messenger, RNA-Binding Proteins, Genome, Alternative Splicing, Neocortex, Genomics, Polyadenylation, Immunoprecipitation, Mice
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