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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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“…covalent crosslinking between proteins and the mRNAs to which they are bound followed by RNP immunoprecipitation and high-throughput sequencing 64,65 — it was shown that FMRP binds most frequently to the coding regions of mRNAs, with fewer binding sites within the 5 ′ and 3 ′ UTRs (the sites…”
BackgroundMethodGraphProt: modeling binding preferences of RNA-binding proteins
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“To test this hypothesis, we compared experimentally derived PTB-binding affinities of two sets of sequences with GraphProt prediction margins using the GraphProt model for PTB HITS-CLIP .”
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“RNA regulatory maps demonstrate that Mbnl splicing activity is position dependent comparable to other alternative splicing factors (Charizanis et al., 2012; Du et al., 2010; Licatalosi et al., 2008; Wang et al., 2012).”
BackgroundResultComprehensive discovery of endogenous Argonaute binding sites in Caenorhabditis elegans
Zisoulis, D. G., Lovci, M., Wilbert, M. L., Hutt, K. R., Liang, T. Y., Pasquinelli, A. E., & Yeo, G. W.-M. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1745 · Cited by 297
“elegans identifies known miRNA targets As miRNAs guide Argonaute proteins to specific complementary sequences in mRNAs, we applied the CLIP-seq (also referred to as HITS-CLIP) metho”
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Self-citationThe snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing
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“A further improvement of the CLIP technique, the individual nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP) (166), is based on the fact that peptide/amino acid residue remaining cross-linked to RNA after proteinase K treatment will block RT.”
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BackgroundLIN28 Binds Messenger RNAs at GGAGA Motifs and Regulates Splicing Factor Abundance
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BackgroundPAR-CliP - A Method to Identify Transcriptome-wide the Binding Sites of RNA Binding Proteins
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“Although not always specifically localized to the nucleus or cytoplasm, other RNA binding proteins have been found to bind introns to affect splicing, as well as 5ʹ or 3ʹ UTRs to affect translation (Ince-Dunn et al., 2012; Licatalosi et al., 2008; Xue et al., 2009).”
BackgroundCompetition between target sites of regulators shapes post-transcriptional gene regulation
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Global changes in the RNA binding specificity of HIV-1 Gag regulate virion genesis
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“CLIP Assay for HIV-1 Gag-RNA Binding We employed recently developed CLIP approaches (Hafner et al., 2010; Licatalosi et al., 2008) to identify RNA molecules bound by HIV-1 Gag protein during particle genesis.”
RNA Chemical Proteomics Reveals the N6-Methyladenosine (m6A)-Regulated Protein–RNA Interactome
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PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs
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The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site
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“For example, NOVA proteins, which are known splicing regulators in the brain (Jensen et al. 2000), were shown to regulate APA by binding to sites in 3′ UTRs and repress or enhance PAS usage in a position-dependent manner (Licatalosi et al. 2008).”
BackgroundAnalysis of CLIP and iCLIP methods for nucleotide-resolution studies of protein-RNA interactions
Sugimoto, Y., König, J., Hussain, S., Zupan, B., Curk, T., Frye, M., & Ule, J. (2012) · Genome Biology · doi:10.1186/gb-2012-13-8-r67 · Cited by 234
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A deep learning framework for modeling structural features of RNA-binding protein targets
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“Recently, the advent of high-throughput experimental methods, such as the cross-linking immunoprecipitation coupled with high-throughput sequencing ( CLIP-seq ) protocols, has greatly advanced the genome-wide studies of RNA–protein interactions (5–8).”
BackgroundiCLIP Predicts the Dual Splicing Effects of TIA-RNA Interactions
Wang, Z., Kayikci, M., Briese, M., Zarnack, K., Luscombe, N. M., Rot, G., Zupan, B., Curk, T., & Ule, J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000530 · Cited by 242
“Unlike Nova, FOX2, and PTB proteins [4,23,24,42], which bind at positions close to either 39 or 59 splice sites, TIA RNA maps did not identify significant binding at 39 splice sites or within the alternative exons.”
BackgroundInfluentialSelf-citationMotif-based analysis of large nucleotide data sets using MEME-ChIP
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“CLIP-seq, also known as HITS-CLIP, screens for cross-linking sites between RBPs and RNA molecules via UV-cross-linking and immunoprecipitation 34,35 .”
BackgroundMethodCLIPdb: a CLIP-seq database for protein-RNA interactions
Yang, Y., Di, C., Hu, B., Zhou, M., Liu, Y., Song, N., Li, Y., Umetsu, J., & Lu, Z. J. (2015) · BMC Genomics · doi:10.1186/s12864-015-1273-2 · Cited by 240
“Although the CLIP-seq data actually contain strandness information [5-7], some peak-calling tools (e.”
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“For example, through binding to clusters of YCAY motifs distributed within specific exon and intron zones, Nova2 can positively or negatively regulate 7% of neural-specific alternative exons in genes that function in the synapse and in axon guidance (Licatalosi et al., 2008; Ule et al., 2005).”
BackgroundConservation of an RNA regulatory map between Drosophila and mammalsPreprint
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“NOVA1/2 has previously been shown to preferentially repress downstream splice sites and activate upstream splice sites (Ule et al. 2006; Licatalosi et al. 2008).”
BackgroundInfluentialThe specificity of long noncoding RNA expression
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“In addition to these core factors, splicing is often dependent on other proteins that can either activate or repress signal recognition, therefore playing a very important role in the regulation of specific events [3,4].”
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Global Patterns of Tissue-Specific Alternative Polyadenylation in Drosophila
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“This raises the possibility of a complex network of auto- and cross-regulating posttranscriptional regulatory factors in the CNS. Recent technical advances in identifying RBP interactions with RNA elements such as PARCLIP and HITS-CLIP (Hafner et al., 2010; Licatalosi et al., 2008) enable genome-wide examination of RB…”
The Spen Family Protein FPA Controls Alternative Cleavage and Polyadenylation of RNA
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Purification of cross-linked RNA-protein complexes by phenol-toluol extraction
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“…it does so in clusters, analogous to the way in which Nova proteins recognize specific targets by binding clusters of low complexity YCAY elements (Licatalosi et al., 2008; Zhang et al., 2010). nElav Regulation of Alternative Splicing Previous studies in Drosophila have indicated that nElavl…”
InfluentialSelf-citationLIN28A Is a Suppressor of ER-Associated Translation in Embryonic Stem Cells
Cho, J., Chang, H., Kwon, S. C., Kim, B., Kim, Y., Choe, J., Ha, M., Kim, Y. K., & Kim, V. N. (2012) · Cell · doi:10.1016/j.cell.2012.10.019 · Cited by 223
“In order to obtain a genome-wide view of LIN28A’s function, we identified LIN28A-interacting RNAs by using a technique that combines UV crosslinking, immunoprecipitation, and highthroughput sequencing (CLIP-seq, also known as HITS-CLIP) (Chi et al., 2009; Licatalosi et al., 2008).”
BackgroundMethodRNA-binding proteins in neurodegeneration: mechanisms in aggregatePreprint
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“Subsequent CLIP analysis of Nova-2 demonstrated a role in both brain-specific splicing and alternative polyadenylation (Licatalosi et al. 2008).”
MethodDGCR8 HITS-CLIP reveals novel functions for the Microprocessor
Macías, S., Plass, M., Stajuda, A., Michlewski, G., Eyras, E., & Cáceres, J. F. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2344 · Cited by 228
RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing
Maatz, H., Jens, M., Liss, M., Schäfer, S., Heinig, M., Kirchner, M., Adami, E., Rintisch, C., Dauksaite, V., Radke, M. H., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74523 · Cited by 221
Buenrostro, J. D., Araya, C. L., Chircus, L. M., Layton, C. J., Chang, H. Y., Snyder, M. P., & Greenleaf, W. J. (2014) · Nature Biotechnology · doi:10.1038/nbt.2880 · Cited by 220
Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions
Ishigaki, S., Masuda, A., Fujioka, Y., Iguchi, Y., Katsuno, M., Shibata, A., Urano, F., Sobue, G., & Ohno, K. (2012) · Scientific Reports · doi:10.1038/srep00529 · Cited by 219
Identification of RNA–protein interaction networks using PAR‐CLIP
Ascano, M., Hafner, M., Čekan, P., Gerstberger, S. C., & Tuschl, T. (2011) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1103 · Cited by 228
Deep mutational scanning: assessing protein function on a massive scale
Araya, C. L., & Fowler, D. M. (2011) · Trends in biotechnology · doi:10.1016/j.tibtech.2011.04.003 · Cited by 219
“and other assays have all been adapted to make use of counting DNA sequence reads as output [3, 14–23].”
MethodLong noncoding RNAs in innate and adaptive immunity
Fitzgerald, K. A., & Caffrey, D. R. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.12.001 · Cited by 223
“Like mRNA, lncRNA can also interact with miRNAs by hybridizing to partially complementary sequences [32,33] Additionally, some miRNAbinding lncRNA have the potential to act as molecular sponges that quench the effects of miRNA on their primary mRNA targets [34–39].”
BackgroundRBFOX1 regulates both splicing and transcriptional networks in human neuronal development
Fogel, B. L., Wexler, E., Wahnich, A., Friedrich, T., Vijayendran, C., Gao, F., Parikshak, N., Konopka, G., & Geschwind, D. H. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds240 · Cited by 216
“On more detailed inspection, we did find upstream enrichment of alternate sequences that NOVA1 has been reported to bind (34) (Supplementary Material, File S2), but in vivo crosslinking and immunoprecipitation experiments do not suggest these to be of functional significance (35).”
BackgroundALS-Associated FUS Mutations Result in Compromised FUS Alternative Splicing and Autoregulation
Zhou, Y., Liu, S., Liu, G., Öztürk, A., & Hicks, G. G. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003895 · Cited by 223
“Out of all 206 FUSassociated cassette exons, 87 cassette exons which are flanked by constitutive exons were used to generate a normalized complexity map as previously described [36].”
MethodQuantitative evaluation of all hexamers as exonic splicing elementsPreprint
Ke, S., Shang, S., Kalachikov, S. M., Morozova, I., Yu, L., Russo, J. J., Ju, J., & Chasin, L. A. (2011) · Genome Research · doi:10.1101/gr.119628.110 · Cited by 204
“Direct functional selections for exonic splicing sequences have been carried out both in vitro (Tian and Kole 1995, 2001; Liu et al. 1998; Schaal and Maniatis 1999; Smith et al. 2006) and in vivo (Coulter et al. 1997; Wang et al. 2004), sometimes tied to responses to specific SR proteins (Liu et…”
BackgroundMethodSystematic discovery of structural elements governing stability of mammalian messenger RNAs
Goodarzi, H., Najafabadi, H. S., Oikonomou, P., Greco, T. M., Fish, L., Salavati, R., Cristea, I. M., & Tavazoie, S. (2012) · Nature · doi:10.1038/nature11013 · Cited by 187
Alternative polyadenylation: New insights from global analyses
Shi, Y. (2012) · RNA · doi:10.1261/rna.035899.112 · Cited by 212
“Another key technology that is critical for mechanistic studies of APA regulation is the global mapping of protein– RNA interactions by UV cross-linking immunoprecipitation coupled with high-throughput sequencing (HITS–CLIP or CLIP–seq) (Ule et al. 2003; Licatalosi et al. 2008).”
BackgroundmRNA transport & local translation in neurons
Glock, C., Heumüller, M., & Schuman, E. M. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.05.005 · Cited by 217
Warzecha, C. C., Shen, S., Xing, Y., & Carstens, R. P. (2009) · RNA Biology · doi:10.4161/rna.6.5.9606 · Cited by 208
“Investigations of other splicing factors that both enhance and silence exons have shown that the location of splicing factor binding with respect to the regulated exon often correlates with the effect it will have on splicing of the exon.(32-34,52) Such “RNA maps” have been shown to be capable of identifying novel spl…”
BackgrounddoRiNA: a database of RNA interactions in post-transcriptional regulation
Anders, G., Mackowiak, S. D., Jens, M., Maaskola, J., Kuntzagk, A., Rajewsky, N., Landthaler, M., & Dieterich, C. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr1007 · Cited by 202
“Additionally, we collect and integrate target sites from published HITS-CLIP experiments (12) and other variants into doRiNA as long as they provide precise positional target site information.”
MethodNeuronal regulation of pre-mRNA splicing by polypyrimidine tract binding proteins, PTBP1 and PTBP2
Keppetipola, N., Sharma, S., Li, Q., & Black, D. L. (2012) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2012.691456 · Cited by 201
“Within the nucleus, these proteins affect large programs of alternative processing events (Ule et al., 2006; Boutz et al., 2007b; Kalsotra et al., 2008; Licatalosi et al., 2008; Xue et al., 2009; Yeo et al., 2009; Kalsotra and Cooper, 2011).”
BackgroundLicatalosi, D. D., Yano, M., Fak, J. J., Mele, A., Grabinski, S. E., Zhang, C., & Darnell, R. B. (2012) · Genes & Development · doi:10.1101/gad.191338.112 · Cited by 193
Self-citationiCLIP - Transcriptome-wide Mapping of Protein-RNA Interactions with Individual Nucleotide Resolution
König, J., Zarnack, K., Rot, G., Curk, T., Kayikci, M., Zupan, B., Turner, D. J., Luscombe, N. M., & Ule, J. (2011) · Journal of Visualized Experiments · doi:10.3791/2638 · Cited by 215
Self-citationPlatforms for Investigating LncRNA Functions
Richard, J. L. C., & Eichhorn, P. J. A. (2018) · SLAS TECHNOLOGY · doi:10.1177/2472630318780639 · Cited by 189
The Emerging Function and Mechanism of ceRNAs in Cancer
Wang, Y., Hou, J., He, D., Sun, M., Zhang, P., Yu, Y., & Chen, Y. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.02.001 · Cited by 187
Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target
Krzyżosiak, W. J., Sobczak, K., Wojciechowska, M., Fiszer, A., Mykowska, A., & Kozłowski, P. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr729 · Cited by 191
“Such methods as global RACE (89), transcriptome-wide RNA structure probing (90) and HITS-CLIP (HIgh-Throughput Sequencing of CrossLinking and ImmunoPrecipitation products) (91) allow detecting products of RNA cleavages by endogenous nucleases or exogenous reagents, and determining high-resolution maps of RNA–protein i…”
MethodTarPmiR: a new approach for microRNA target site prediction
Ding, J., Li, X., & Hu, H. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw318 · Cited by 171
“For instance, miRTarCLIP (Chou et al., 2013) identifies miRNA target sites from the data generated by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) experiments (Chi et al., 2009; Licatalosi et al., 2008) and photoactivatableribonucleoside-enhanced…”
BackgroundFox-1 family of RNA-binding proteins
Kuroyanagi, H. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0120-5 · Cited by 187
“These stories are reminiscent of the CLIP-seq analysis of NOVA that led to the discovery that NOVA interacts with 30 UTRs of target mRNAs and regulates alternative polyadenylation in the brain [43].”
MethodMisregulated RNA processing in amyotrophic lateral sclerosis
Polymenidou, M., Lagier-Tourenne, C., Hutt, K. R., Bennett, C. F., Cleveland, D. W., & Yeo, G. W. (2012) · Brain Research · doi:10.1016/j.brainres.2012.02.059 · Cited by 169
“Indeed, using cross-linking, immunoprecipitation and high-throughput sequencing or CLIP-seq (Ule et al., 2003; Licatalosi et al., 2008; Yeo et al., 2009) or an alternative technique that omits the crosslinking step (RNA-immunoprecipitation or RIP-seq), TDP-43 RNA targets within the normal central…”
MethodNova2 Regulates Neuronal Migration through an RNA Switch in Disabled-1 Signaling
Yano, M., Hayakawa-Yano, Y., Mele, A., & Darnell, R. B. (2010) · Neuron · doi:10.1016/j.neuron.2010.05.007 · Cited by 176
Self-citationRNA Protein Interaction in Neurons
Darnell, R. B. (2013) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062912-114322 · Cited by 181
“These studies, subsequently combined with HITS-CLIP (Licatalosi et al., 2008), and more sophisticated computational methods (e.g. Bayesian network analysis of NOVA datasets; (Zhang et al., 2010)) led to the identification of a robust set of ~700 alternative exons and a smaller number of alternative…”
BackgroundMethodSelf-citationPreitner, N., Quan, J., Nowakowski, D. W., Hancock, M., Shi, J., Tcherkezian, J., Young‐Pearse, T. L., & Flanagan, J. G. (2014) · Cell · doi:10.1016/j.cell.2014.05.042 · Cited by 176
“…uses UV crosslinking to identify RNAs directly bound to a protein of interest in the native context of cells or tissues, followed by highthroughput sequencing (Licatalosi et al., 2008; Darnell, 2013), although the understanding of neural protein-RNA regulatory networks remains at an early stage.”
BackgroundMethodDeciphering the role of RNA-binding proteins in the post-transcriptional control of gene expression
Kishore, S., Luber, S., & Zavolan, M. (2010) · Briefings in Functional Genomics · doi:10.1093/bfgp/elq028 · Cited by 186
“role of NOVA in alternative polyadenylation of transcripts in the brain [93].”
CLIP Tool Kit (CTK): a flexible and robust pipeline to analyze CLIP sequencing data
Shah, A., Qian, Y., Weyn‐Vanhentenryck, S. M., & Zhang, C. (2016) · Bioinformatics · doi:10.1093/bioinformatics/btw653 · Cited by 182
QAPA: a new method for the systematic analysis of alternative polyadenylation from RNA-seq data
Ha, K., Blencowe, B. J., & Morris, Q. (2018) · Genome biology · doi:10.1186/s13059-018-1414-4 · Cited by 184
“For example, specific splicing regulators such as SRRM1 [42] and NOVA [43] control 3′-end formation, and components of the cleavage polyadenylation machinery can influence splicing [44–46].”
BackgroundWebb, S., Hector, R. D., Kudla, G., & Granneman, S. (2014) · Genome biology · doi:10.1186/gb-2014-15-1-r8 · Cited by 185
“has markedly increased the sensitivity of the methodology and provided an unparalleled capability to identify protein-RNA interactions transcriptome-wide [3,5,7].”
BackgroundAlternative splicing: decoding an expansive regulatory layer
Irimia, M., & Blencowe, B. J. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.03.005 · Cited by 177
“[46 ,47 ,48] describe methods coupling highthroughput RNA sequencing to in vivo cross-linking and immunoprecipitation of RBPs.”
MethodXiao, R., Tang, P., Yang, B., Huang, J. S., Zhou, Y., Shao, C., Li, H., Sun, H. Z., Zhang, Y., & Fu, X. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.01.009 · Cited by 177
“…by performing crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq), which has been instrumental in identifying in vivo targets for RNA-binding proteins and elucidating rules in regulated splicing (Licatalosi et al., 2008; Wang et al., 2010; Xue et al., 2009; Yeo et al., 2009).”
CUGBP1 and MBNL1 preferentially bind to 3′ UTRs and facilitate mRNA decay
Masuda, A., Andersen, H. S., Doktor, T. K., Okamoto, T., Ito, M., Andresen, B. S., & Ohno, K. (2012) · Scientific Reports · doi:10.1038/srep00209 · Cited by 174
“High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP”
MethodTandem Stem-Loops in roX RNAs Act Together to Mediate X Chromosome Dosage Compensation in Drosophila
Ilik, İ., Quinn, J. J., Georgiev, P., Tavares-Cadete, F., Maticzka, D., Toscano, S., Wan, Y., Spitale, R. C., Luscombe, N. M., Backofen, R., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.07.001 · Cited by 176
“Based on SHAPE, iCLIP, and HITS-CLIP data, RNA was split into two halves.”
InfluentialThe Ded1/DDX3 subfamily of DEAD-box RNA helicases
Sharma, D., & Jankowsky, E. (2014) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2014.931339 · Cited by 177
“This appears feasible, given the progress of next generation sequencing techniques to probe translation and protein binding to cellular RNA (Ingolia, 2014; Licatalosi et al., 2008).”
BackgroundCleavage and polyadenylation: Ending the message expands gene regulation
Neve, J., Patel, R. J., Wang, Z., Louey, A., & Furger, A. (2017) · RNA Biology · doi:10.1080/15476286.2017.1306171 · Cited by 185
The helicase Ded1p controls use of near-cognate translation initiation codons in 5′ UTRs
Guenther, U., Weinberg, D. E., Zubradt, M., Tedeschi, F. A., Stawicki, B. N., Zagore, L. L., Brar, G. A., Licatalosi, D. D., Bartel, D. P., Weissman, J. S., et al. (2018) · Nature · doi:10.1038/s41586-018-0258-0 · Cited by 172
“Sequencing reads were processed as described previously 37,39 .”
Self-citationLong Noncoding RNAs : Insights from Biological Features and Functions to Diseases
Li, X., Wu, Z., Fu, X., & Han, W. (2012) · Medicinal Research Reviews · doi:10.1002/med.21254 · Cited by 172
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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