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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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“This method, termed CLIP10,11, uses UV-irradiation to induce covalent crosslinks between protein-RNA complexes in situ , allowing rigorous purification of RNABPs along with small fragments of RNA, which can be amplified and sequenced.”
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RNA sequencing: from tag-based profiling to resolving complete transcript structure
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“Most of the CLIP-based studies performed so far focus on splicing factors [108, 109, 114].”
BackgroundMethodYano, M., Hayakawa‐Yano, Y., & Okano, H. (2016) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2016.01.002 · Cited by 35
Recurrent rewiring and emergence of RNA regulatory networks
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“We cross-linked RNA–protein complexes in vivo with UV irradiation of intact cells, immunopurified these protein–RNA complexes, and identified the RNAs by high throughput sequencing (“HITS-CLIP”) (49).”
MethodInfluentialProbing Long Non-coding RNA-Protein Interactions
Barra, J., & Leucci, E. (2017) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2017.00045 · Cited by 37
A mechanism underlying position-specific regulation of alternative splicing
Hamid, F., & Makeyev, E. V. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx901 · Cited by 33
“For example, transcriptome-wide crosslinking-immunoprecipitation (CLIP) studies combined with systematic analyses of splicing patterns showed that RBPs from the NOVA family often repress alternative exons when recruited to an upstream intronic position or the exon itself and promote their inclusion into mature mRNA wh…”
BackgroundNoncoding RNAs in the Regulatory Network of Hypertension
Wu, G., José, P. A., & Zeng, C. (2018) · Hypertension · doi:10.1161/hypertensionaha.118.11126 · Cited by 32
Capelari, É. F., da Fonseca, G. C., Guzmán, F., & Margis, R. (2019) · Plants · doi:10.3390/plants8090302 · Cited by 34
“The lncRNAs are usually more than 300 nucleotides in length and can be regulated by microRNAs (miRNAs) [2,3].”
BackgroundAll's well that ends well: alternative polyadenylation and its implications for stem cell biology
Mueller, A. A., Cheung, T. H., & Rando, T. A. (2013) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.12.008 · Cited by 32
Definition of RNA Polymerase II CoTC Terminator Elements in the Human Genome
Nojima, T., Dienstbier, M., Murphy, S., Proudfoot, N. J., & Dye, M. J. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.03.012 · Cited by 32
“Here we have used a CLIP-seq strategy (Licatalosi et al., 2008) to distinguish pre-mRNAs that are released from the DNA template before cleavage at the poly(A) site, in order to identify genes that utilize the CoTC termination pathway.”
MethodInfluentialRBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression
Tarn, W., Kuo, H., Yu, H.-I., Liu, S.-W., Tseng, C.-T., Dhananjaya, D., Hung, K.-Y., Tu, C., Chang, S.-H., Huang, G., et al. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-11-0798 · Cited by 32
“Nova binds to YCAY nucleotide sequences (Y stands for pyrimidine) near regulated exons, and its binding shows positiondependent effects on splicing regulation (Licatalosi et al., 2008; Yano et al., 2010).”
BackgroundPilaz, L., & Silver, D. L. (2017) · FEBS Letters · doi:10.1002/1873-3468.12626 · Cited by 31
RPI-Bind: a structure-based method for accurate identification of RNA-protein binding sites
Luo, J., Liu, L., Venkateswaran, S., Song, Q., & Zhou, X. (2017) · Scientific Reports · doi:10.1038/s41598-017-00795-4 · Cited by 32
Recent computational developments on CLIP-seq data analysis and microRNA targeting implications
Bottini, S., Pratella, D., Grandjean, V., Repetto, E., & Trabucchi, M. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx063 · Cited by 32
Roberts, J. T., Porman, A. M., & Johnson, A. M. (2020) · RNA · doi:10.1261/rna.078543.120 · Cited by 32
“Instead of addition of both sequencing adapters to the original RNA fragments as in m 6 A-CLIP (based on HITS-CLIP [Licatalosi et al. 2008]), or using circular ligation as implemented in miCLIP (based on iCLIP), our meCLIP protocol (based on eCLIP) adds adapters for sequencing in two separate steps.”
Characterization of the Regulation of CD46 RNA Alternative Splicing
Tang, S. J., Luo, S., Ho, J. X. J., Ly, P. T., Goh, E., & Roca, X. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.710350 · Cited by 32
PrismNet: predicting protein–RNA interaction using in vivo RNA structural information
Xu, Y., Zhu, J., Huang, W., Xu, K., Yang, R., Zhang, Q. C., & Sun, L. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad353 · Cited by 31
Roles and regulation of microRNAs in cytomegalovirus infection
Tuddenham, L., & Pfeffer, S. (2011) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.04.002 · Cited by 31
Target selection by natural and redesigned PUF proteins
Porter, D. F., Koh, Y. Y., VanVeller, B., Raines, R. T., & Wickens, M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508501112 · Cited by 31
“cerevisiae Puf2p, we performed HITS-CLIP and PAR-CLIP with strains expressing a C-terminally tagged Puf2p allele at the PUF2 genomic locus (18, 19).”
MethodComputational Prediction of Functional MicroRNA–mRNA Interactions
Demirci, M. D. S., Yousef, M., & Allmer, J. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-8982-9_7 · Cited by 31
uvCLAP is a fast and non-radioactive method to identify in vivo targets of RNA-binding proteins
Maticzka, D., Ilik, İ., Aktaş, T., Backofen, R., & Akhtar, A. (2018) · Nature Communications · doi:10.1038/s41467-018-03575-4 · Cited by 33
RNA-binding protein signaling in adult neurogenesis
Chan, J. N.-M., Sánchez-Vidaña, D. I., Anoopkumar‐Dukie, S., Li, Y., & Wui-Man, L. B. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.982549 · Cited by 34
“Neurons have the ability to adjust neuronal output and consolidate alterations in synaptic connections thanks to local protein synthesis (Bramham and Wells, 2007; Licatalosi et al., 2008).”
BackgroundMolecular and Genetic Analysis of the Drosophila Model of Fragile X Syndrome
Tessier, C. R., & Broadie, K. S. (2011) · Results and problems in cell differentiation · doi:10.1007/978-3-642-21649-7_7 · Cited by 31
“Also promising is the rapidly advancing technology of RNA-Seq which can provide direct sequence analysis of dFMRP-bound transcripts as has been done previously with the splicing factor NOVA (Licatalosi et al. 2008; Marioni et al. 2008; Wang et al. 2009).”
Carazo, F., Romero, J. P., & Rubio, Á. (2018) · Briefings in Bioinformatics · doi:10.1093/bib/bby005 · Cited by 30
Koo, P. K., Anand, P., Paul, S. B., & Eddy, S. R. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/418459 · Cited by 31
“…in vivo experimental methods enrich for protein-bound RNA sequences (Lambert et al, 2014; Tome et al, 2014; Guenther et al, 2013; Ray et al, 2017; Licatalosi et al, 2008; Hafner et al, 2010; Konig et al, 2010; Sundararaman et al, 2016), and computational methods are used to deduce the consensus…”
MethodSun, T., Li, Q., Geisinger, J. M., Hu, S.-B., Fan, B., Su, S., Tsui, W., Guo, H., Ma, J., & Li, J. B. (2025) · Nature Genetics · doi:10.1038/s41588-025-02430-9 · Cited by 55
“To identify immunogenic dsRNAs, direct approaches that capture MDA5-bound dsRNA, such as CLIP, are hindered by the promiscuous binding of monomeric MDA5 to ssRNA and dsDNA 34,35 .”
siRNA Genome Screening Approaches to Therapeutic Drug Repositioning
Perwitasari, O., Bakre, A. A., Tompkins, S. M., & Tripp, R. A. (2013) · Pharmaceuticals · doi:10.3390/ph6020124 · Cited by 30
“Novel alternate approaches to identify true miRNA targets are based on isolating miRNA:target transcript pairs from RISC complexes using techniques as HITS-CLIP [19] or PAR-CLIP [20] and next generation sequencing tools.”
MethodIntegrating Epigenomics into the Understanding of Biomedical Insight
Han, Y., & He, X. (2016) · Bioinformatics and Biology Insights · doi:10.4137/bbi.s38427 · Cited by 32
“The application of CLIP-seq is expanding from mRNA to miRNA, 144 lncRNA, 145 cirRNA, 146 and mitochondrial RNA.”
BackgroundInfluentialInterplay between K-RAS and miRNAs
Shui, B., Rocca, G. L., Ventura, A., & Haigis, K. M. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.01.002 · Cited by 30
A systematic benchmark of machine learning methods for protein–RNA interaction prediction
Horlacher, M., Cantini, G., Hesse, J., Schinke, P., Goedert, N., Londhe, S., Moyon, L., & Marsico, A. (2023) · Briefings in Bioinformatics · doi:10.1093/bib/bbad307 · Cited by 31
“[39] datasets, it includes data derived from different CLIP-seq protocols, including PAR-CLIP [15], iCLIP [6] and HITSCLIP [66].”
MethodOf social molecules: The interactive assembly ofASH1mRNA-transport complexes in yeast
Niedner, A., Edelmann, F. T., & Niessing, D. (2014) · RNA Biology · doi:10.4161/rna.29946 · Cited by 33
Selective and flexible depletion of problematic sequences from RNA-seq libraries at the cDNA stage
Archer, S., Shirokikh, N., & Preiss, T. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-401 · Cited by 34
“The costs of obtaining custom modified probes to, for instance, target all rRNA fragments in degraded (e.g. archival samples) or digested samples (e.g. for CLIP-seq or ribosome profiling) are prohibitive.”
BackgroundInfluentialGenomic analysis of RNA localization
Taliaferro, J. M., Wang, E. T., & Burge, C. B. (2014) · RNA Biology · doi:10.4161/rna.32146 · Cited by 32
Regulation of Protein Levels in Subcellular Domains through mRNA Transport and Localized Translation
Willis, D. E., & Twiss, J. L. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.r900005-mcp200 · Cited by 30
“Deep sequencing of RNAs isolated through cross-linking and immunoprecipitation brings the potential to identify RNA motifs that are directly targeted by RNA-binding proteins because the protected regions are indicative of protein binding sites (108, 109).”
BackgroundPurifying Selection on Exonic Splice Enhancers in Intronless Genes
Savisaar, R., & Hurst, L. D. (2016) · Molecular Biology and Evolution · doi:10.1093/molbev/msw018 · Cited by 30
“Techniques now exist that enable the experimental investigation of genome-wide RNA-protein interactions in vivo Savisaar and Hurst . doi:10.1093/molbev/msw018 MBE 1410Downloaded from https://academic.oup.com/mbe/article-abstract/33/6/1396/2579317 by guest on 30 July 2018 through the ultraviolet crosslinking of interac…”
BackgroundInfluentialIllustrating the Epitranscriptome at Nucleotide Resolution Using Methylation-iCLIP (miCLIP)
George, H., Ule, J., & Hussain, S. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6807-7_7 · Cited by 30
“Initially described for the use of detecting protein-RNA interactions, efficient CLIP-based techniques employed UV covalent crosslinking to enable the RNA interaction partners of a protein of interest to be identified with high stringency and at a remarkably high signal to noise ratio (13,14).”
MethodSelf-citationWang, Z., & Lei, X. (2021) · BMC Bioinformatics · doi:10.1186/s12859-020-03942-3 · Cited by 29
Cipriano, A., & Ballarino, M. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00020 · Cited by 29
“…when the first CLIP approach was used on brain tissues (Ule et al., 2003), many variants of CLIP-based approaches have been developed which combine CLIP experiments with high-throughput sequencing (HITS)-CLIP (also known as CLIPseq) (Licatalosi et al., 2008; Chi et al., 2009; Guil et al., 2012).”
BackgroundMethodA Model-Based Approach to Identify Binding Sites in CLIP-Seq Data
Wang, T., Chen, B., Kim, M., Xie, Y., & Xiao, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093248 · Cited by 27
“high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) [5,8,9], and 2.”
BackgroundMethodUnravelling adverse reactions to NSAIDs using systems biology
Perkins, J. R., Sanak, M., Cantó, G., Blanca, M., & Cornejo-García, J. A. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.12.003 · Cited by 28
Lou, T., Weidmann, C. A., Killingsworth, J., Hall, T. M. T., Goldstrohm, A. C., & Campbell, Z. T. (2016) · Methods · doi:10.1016/j.ymeth.2016.10.001 · Cited by 28
NMR solution structure determination of large RNA-protein complexes
Yadav, D. K., & Lukavsky, P. J. (2016) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2016.10.001 · Cited by 29
“In addition, genome-wide approaches such as HITS-CLIP [58], PAR-CLIP [59], iCLIP [60] and hiCLIP [61] are powerful methods to identify ssRNA and dsRNA binding motifs for individual RBPs in vivo.”
MethodT-ALL and thymocytes: a message of noncoding RNAs
Wallaert, A., Durinck, K., Taghon, T., Vlierberghe, P. V., & Speleman, F. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0432-0 · Cited by 29
“High-troughput sequencing methods used for miRNA-mRNA interaction detection are for example HITS-CLIP (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation) [95] or PAR-CLIP (photoactivatable ribonucleosideenhanced crosslinking and immunoprecipitation) [96], which are methods developed to ide…”
MethodEvolution of Alternative Splicing in Eudicots
Ling, Z., Brockmöller, T., Baldwin, I. T., & Xu, S. (2019) · Frontiers in Plant Science · doi:10.3389/fpls.2019.00707 · Cited by 29
“1) (Lindgreen, 2012) with parameters “–collapse –trimns – trimqualities 2 –minlength 36.””
The Landscape of RNA-Protein Interactions in Plants: Approaches and Current Status
Burjoski, V. E. E., & Reddy, A. S. N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062845 · Cited by 31
“This allowed the identification of over 1000-fold more unique binding sites compared to CLIP with traditional sequencing techniques, although this leaves one with the opposite problem—a plethora of data to sift through and discern signal from noise [20].”
BackgroundShakola, F., Suri, P., & Ruggiu, M. (2015) · Biomolecules · doi:10.3390/biom5032073 · Cited by 28
“Using publicly available CLIP-seq whole genome data [182], SNCA appears to have several PTB CLIP tags in intron 4 upstream of alternatively spliced exon 5.”
MethodInfluentialDiscovering RNA-Protein Interactome by Using Chemical Context Profiling of the RNA-Protein Interface
Parisien, M., Wang, X., Perdrizet, G., Lamphear, C., Fierke, C. A., Maheshwari, K. C., Wilde, M. J., Sosnick, T. R., & Pan, T. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.010 · Cited by 28
“1710 Cell Reports 3, 1703–1713, May 30, 2013 ª2013 The Authors The six tRNA-binding proteins have broad binding selectivity for tRNA, similar to many mRNA-binding proteins that recognize broad sequence/structural motifs in manymRNAs (Ascano et al., 2012; Licatalosi et al., 2008).”
BackgroundSelf-citationLin, H.-C., Zhao, J., Niland, C. N., Tran, B., Jankowsky, E., & Harris, M. E. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2016.09.002 · Cited by 27
“Significant progress has been made in defining protein binding sites within the transcriptomes of cells (Ascano et al., 2012; Licatalosi et al., 2008; Zhao et al., 2010).”
From parts lists to functional significance—RNA–protein interactions in gene regulation
Kilchert, C., Sträßer, K., Kunetsky, V., & Änkö, M. (2019) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1582 · Cited by 26
“…development of UV crosslinking and immunoprecipitation methods (CLIP-sequencing in its various forms) (Hafner et al., 2010; Huppertz et al., 2014; Licatalosi et al., 2008; Ule, Jensen, Mele, & Darnell, 2005; Van Nostrand et al., 2016), including the comprehensive survey of RBP binding sites by…”
MethodExtensive cross-regulation of post-transcriptional regulatory networks in DrosophilaPreprint
Stoiber, M. H., Olson, S., May, G. E., Duff, M. O., Manent, J., Obar, R. A., Guruharsha, K. G., Bickel, P. J., Artavanis‐Tsakonas, S., Brown, J. B., et al. (2015) · Genome Research · doi:10.1101/gr.182675.114 · Cited by 28
“Some RBPs have strong sequence specificity for cognate binding sites, including NOVA2 and the fly homolog PS, which bind to YCAY repeats in species from insects to mammals, although the RNA targets regulated by NOVA2 and PS have changed substantially across metazoans (Buckanovich and Darnell 1997; Brooks et al. 2011).”
RNA regulons and the RNA-protein interaction network
Imig, J., Kanitz, A., & Gerber, A. P. (2012) · BioMolecular Concepts · doi:10.1515/bmc-2012-0016 · Cited by 28
“Two of these methods, termed c rossl inkingi mmuno p urifi cation (CLIP) (42) and, if high-throughput sequencing is applied, HITS-CLIP, were originally established by Robert Darnell and colleagues (43, 44) .”
BackgroundMethodGenome‐wide approaches in the study of microRNA biology
Wilbert, M. L., & Yeo, G. W.-M. (2010) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.128 · Cited by 29
Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets
Zhang, M., Wang, T., Xiao, G., & Xie, Y. (2020) · Genes · doi:10.3390/genes11010054 · Cited by 26
“HITS-CLIP [14], PAR-CLIP [15] and iCLIP [16] are the three main variants of CLIP-Seq that have been extensively used to identify RBP binding targets, and this has led to deep insights into cellular mechanisms and disease etiology. eCLIP [17], irCLIP [18], and sCLIP [19] are recent advancements in CLIP-Seq technology,…”
MethodIn vivo discovery of RNA proximal proteins via proximity-dependent biotinylation
Lin, X., Fonseca, M. A., Breunig, J. J., Corona, R. I., & Lawrenson, K. (2021) · RNA Biology · doi:10.1080/15476286.2021.1917215 · Cited by 35
“Use of these tools together with protein-centric methods [126,127] and annotation of RNA structure [128,129] will shed light on the mechanisms and regulation of lncRNA functions, RRNA–proteininteractions,”
MethodPezoulas, V. C., Hazapis, O. G., Lаgopati, N., Exarchos, T. P., Goules, A. V., Tzioufas, A. G., Fotiadis, D. I., Stratis, I. G., Yannacopoulos, A. N., & Gorgoulis, V. G. (2021) · Cancer Genomics & Proteomics · doi:10.21873/cgp.20284 · Cited by 29
“Similarly, DeepCLIP (55) applies a similar network architecture that uses 1D convolutional layers to find and enhance features of a set of presented sequences.”
MethodInfluentialCombinatorial Mutagenesis of MBNL1 Zinc Fingers Elucidates Distinct Classes of Regulatory Events
Purcell, J., Oddo, J. C., Wang, E. T., & Berglund, J. A. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00274-12 · Cited by 29
“(53, 54), Nova1/Nova2 (Nova1/2) (24, 46), and the polypyrimi-”
Computational biology of RNA interactions
Dieterich, C., & Stadler, P. F. (2012) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1147 · Cited by 28
“83 Herein, RNA target sites are covalently cross-linked to their respective protein binding partner, which protects them from RNAse digestion.”
BackgroundPOS-1 and GLD-1 repressglp-1translation through a conserved binding-site cluster
Farley, B. M., & Ryder, S. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-03-0216 · Cited by 26
Jereb, S., Hwang, H., Otterloo, E. V., Govek, E., Fak, J. J., Yuan, Y., Hatten, M. E., & Darnell, R. B. (2018) · eLife · doi:10.7554/elife.34042 · Cited by 25
“, 2016) and CLIP (Licatalosi et al., 2008; Ule et al., 2003) – enables purification and sequencing of 3’UTR ends of polyadenylated transcripts via their interaction with poly-A binding protein cytoplasmic 1 (PABPC1), a protein that binds with high specificity to mRNA poly(A) tails.”
BackgroundSelf-citationQuantitative proteomics: a tool to assess cell differentiation
Vermeulen, M., & Selbach, M. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.09.003 · Cited by 26
“A popular method to study RNA–protein interactions is to purify proteins and identify associated RNAs by microarrays or deep sequencing using methods such as crosslinking immunoprecipitation (CLIP) or RNP immunoprecipitation (RIP) [35,36].”
Nelson, P. T., Kiriakidou, M., Mourelatos, Z., Tan, G. S., Jennings, M. H., Xie, K., & Wang, W. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.108 · Cited by 26
“Some methods of high-throughput PmiT identification would side-step the dependence on stable miRNA:mRNA interaction, most notably the HITS-CLIP method that uses ultraviolet (UV) cross-linking and downstream identification of miRNA-bound mRNAs (see below).”
MethodInfluentialKanitz, A., & Gerber, A. P. (2009) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.55 · Cited by 27
Culler, S. J., Hoff, K. G., Voelker, R. B., Berglund, J. A., & Smolke, C. D. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq248 · Cited by 26
“In addition, experiments coupling highthroughput sequencing with cross-linking immunoprecipitation (CLIP) have led to the identification of functional protein-RNA interactions in vivo for a small subset of trans-acting splicing factors (8,9).”
A multiprotein occupancy map of the mRNP on the 3′ end of histone mRNAs
Brooks, L., Lyons, S. M., Mahoney, J. M., Welch, J. D., Liu, Z., Marzluff, W. F., & Whitfield, M. L. (2015) · RNA · doi:10.1261/rna.053389.115 · Cited by 26
“HITS-CLIP (Licatalosi et al. 2008) involves amplifying the nuclease-resistant RNA fragments for highthroughput sequencing (Fig.”
MethodIMP2 axonal localization, RNA interactome, and function in the development of axon trajectories
Preitner, N., Quan, J., Li, X., Nielsen, F. C., & Flanagan, J. G. (2016) · Development · doi:10.1242/dev.128348 · Cited by 25
“2A) (Licatalosi et al., 2008).”
Savisaar, R., & Hurst, L. D. (2017) · Molecular Biology and Evolution · doi:10.1093/molbev/msx061 · Cited by 24
“Although many of these proteins interact preferentially with untranslated regions (UTRs) or introns (Licatalosi et al. 2008; Xue et al. 2009; Ince-Dunn et al. 2012), others primarily bind CDSs (Grellscheid et al.”
BackgroundInfluentialLi, S., Dong, F., Wu, Y., Zhang, S., Zhang, C., Liu, X., Jiang, T., & Zeng, J. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx492 · Cited by 25
“[5] Donny D Licatalosi, Aldo Mele, John J Fak, Jernej Ule, Melis Kayikci, Sung Wook Chi, Tyson A Clark, Anthony C Schweitzer, John E Blume, Xuning Wang, et al.”
BackgroundDiscovery of Allele-Specific Protein-RNA Interactions in Human Transcriptomes
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mRNA Processing: An Emerging Frontier in the Regulation of Pancreatic β Cell Function
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“2c and d. Rbfox proteins regulate AS by binding to conserved (U)GCAUG elements in the transcript [107, 127, 177].”
BackgroundSystematic characterization of cancer transcriptome at transcript resolution
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When Ribonucleases Come into Play in Pathogens: A Survey of Gram-Positive Bacteria
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Sei, E., Wang, T., Hunter, O. V., Xie, Y., & Conrad, N. K. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004652 · Cited by 26
“HITS-CLIP analysis controls for reassortment of RNAs and proteins in extract by employing ultraviolet (UV) irradiation to covalently crosslink proteins to their ligand RNAs.”
MethodInfluentialSystems Biology-Derived Discoveries of Intrinsic Clocks
Millius, A., & Ueda, H. R. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00025 · Cited by 27
Regulation of splicing and circularisation of RNA in epithelial mesenchymal plasticity
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An Overview of Methodologies in Studying lncRNAs in the High-Throughput Era: When Acronyms ATTACK!
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“Most notably, trans-acting proteins such as the NOVA (3–6), the RBFOX (7) and SR protein (8–11) families, and a number of hnRNP (12,13) proteins compete to bind nascent RNAs at specific motifs and drive regulation of alternative splicing in a tissue and developmentally specific manner.”
BackgroundRNAProt: an efficient and feature-rich RNA binding protein binding site predictor
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“In this regard, CLIP-seq (cross-linking and immunoprecipitation followed by next-generation sequencing) [8], together with its popular modifications photoactivatable-ribonucleosideenhanced cross-linking and immunoprecipitation (PAR-CLIP) [9], individual-nucleotide resolution UV cross-linking and immunoprecipitation (i…”
MethodPlant Ribonomics: Proteins in Search of RNA Partners
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“High-throughput sequencing (HITS) combined with CLIP (HITS-CLIP) has potential to generate transcriptome-wide mapping of RNA–protein interactions (31,32).”
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HITS-CLIP (CLIP-Seq) for Mouse Piwi Proteins
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“RNAs targeted by RNA-binding proteins (RBPs), but also the exact nucleotide sequences, at unprecedented resolution [ 15 – 17 ].”
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“95,96 By expanding the analyses, miRNA–target interactions can be elaborated into regulatory networks that can be combined with other types of regulatory interactions.”
BackgroundRegulation of gene expression through production of unstable mRNA isoforms
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Using high-density exon arrays to profile gene expression in closely related species
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“0 array (Gene) 6 PM probes 18 225 (20) 16 979 (15) 12 437 (12) 8984 (10) 11 PM probes 15 264 (22) 10 488 (20) 6978 (17) 4241 (15)”
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“HITS-CLIP also has become an indispensable tool for the investigation of molecular mechanisms and biologic roles of RBPs [3–5].”
Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11
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“For example, mammalian NOVA1 and NOVA2 are neural-enriched RNAbinding proteins that control mRNA alternative splicing (Licatalosi et al., 2008), but NOVA2 also regulates APA by binding nearby proximal PAS in developing mouse brain (Ule et al.”
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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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