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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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“They include either exons affected in DM, namely SOS1 exon 26 and KIF13A exon 21 (39) or unaffected in DM, PPP3CB exon 13 (PTBP2-sensitive) (41), APLP2 exon 14 (NOVA1sensitive) (42), ECT2 exon 4 (FOX2-sensitive) (43) (Supplementary Figure S2c).”
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“Identification of other mRNAs bound by CPEB3 using the UVcross-linking procedure coupled with high throughout sequencing (HITS-CLIP) (Ule et al., 2003; Licatalosi et al., 2008) is currently in progress.”
MethodThe regulatory impact of RNA-binding proteins on microRNA targeting
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BackgroundInfluentialA quantitative RNA code for mRNA target selection by the germline fate determinant GLD‐1
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BackgroundmiRTrace reveals the organismal origins of microRNA sequencing data
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Self-citationHigh-throughput characterization of protein-RNA interactions
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A 5′ cytosine binding pocket in Puf3p specifies regulation of mitochondrial mRNAs
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BackgroundThe Properties of Long Noncoding RNAs That Regulate Chromatin
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BackgroundNova1 is a master regulator of alternative splicing in pancreatic beta cells
Villate, O., Turatsinze, J., Mascali, L. G., Grieco, F. A., Nogueira, T. C., Cunha, D. A., Nardelli, T. R., Sammeth, M., Salunkhe, V. A., Esguerra, J. L. S., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku861 · Cited by 80
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“NOVA appears to control both alternative splicing (Ule et al., 2005) and selection of polyadenylation sites to generate brainspecific 3′-UTR of mRNAs through binding of YCAY clusters, which influences both U2 and U1 recruitment (Licatalosi et al., 2008).”
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“Recent advances in ‘ribonomic’ technologies, such as cross-linking immunoprecipitation high-throughput sequencing (CLIP-seq, also referred to as HITS-CLIP) [5], individual-nucleotide resolution CLIP (iCLIP) [6], and photoactivatable-ribonucleoside-enhanced CLIP”
BackgroundThe Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina
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“This method has been used to identify Argonaute binding sites in mammalian tissues (Licatalosi et al., 2008) and has been adapted for C. elegans (Zisoulis et al., 2010).”
MethodRBP-Maps enables robust generation of splicing regulatory maps
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“For example, polyadenylation analysis implicated splicing regulator NOVA in regulation of alternative polyadenylation (Licatalosi et al. 2008) and recently yielded insight into how binding of TARDBP/TDP43 shows differential regulation of alternative polyadenylation based on whether binding is close to, or further down…”
BackgroundMethodInfluentialIdentification of RNA Helicase Target Sites by UV Cross-Linking and Analysis of cDNA
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p38 MAPK Controls Prothrombin Expression by Regulated RNA 3′ End Processing
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“…were detunicated in cold Hank’s balanced salt solution (HBSS) and seminiferous tubules UV irradiated on ice. Cross-linking, immunoprecipitation with anti-Ptbp2 (Polydorides et al., 2000), and cDNA library construction steps were performed as previously described (Licatalosi et al., 2008, 2012).”
InfluentialSelf-citationDarnell, R. B., Ke, S., & Darnell, J. E., Jr. (2017) · RNA · doi:10.1261/rna.065219.117 · Cited by 76
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BackgroundSelf-citation“Seq-ing” Insights into the Epigenetics of Neuronal Gene Regulation
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“Recently, CLIP-seq [20] has become the standard experimental procedure, with several variants including HITS-CLIP [20], PAR-CLIP [21], and iCLIP [22].”
MethodElements and machinery of non‐coding RNAs: toward their taxonomy
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“To this end, recent technologies for genome-wide analyses of RNA structures [255 – 257], RNA modifications [258 – 263], and RNA – protein interactions [264 – 266] will be without doubt powerful tools for identifying RNA elements and RNP machineries.”
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Self-citationDesign and bioinformatics analysis of genome-wide CLIP experiments
Wang, T., Xiao, G., Chu, Y., Zhang, M. Q., Corey, D. R., & Xie, Y. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv439 · Cited by 77
“The combination of CLIP with NGS technology has greatly improved our ability to study RBP–RNA interactions on the genome scale (22).”
BackgroundMethodNoncanonical transcript forms in yeast and their regulation during environmental stress
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“As expected, most reads from the standard mRNA-seq method originated from inside ORFs (92% of mapped reads), whereas a majority of sequencing reads from our 39-end RNA-seq procedure mapped within a few hundred base pairs downstream from ORF ends (Fig.”
BackgroundInfluentialMechanistic determinants of MBNL activity
Sznajder, Ł. J., Michalak, M., Taylor, K., Cywoniuk, P., Kabza, M., Wojtkowiak-Szlachcic, A., Matłoka, M., Konieczny, P., & Sobczak, K. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw915 · Cited by 76
“Note that Multi MIB also contains crosslinking induced mutations (CIMs), MBNL1-RIP-seq and CLIP-seq results for CELF1 (8) and NOVA (58) proteins.”
BackgroundEmerging Roles for 3′ UTRs in Neurons
Bae, B., & Miura, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103413 · Cited by 77
Grellscheid, S. N., Dalgliesh, C., Storbeck, M., Best, A. J., Liu, Y., Jakubik, M., Mende, Y., Ehrmann, I. E., Curk, T., Roßbach, K., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002390 · Cited by 75
“HITS-CLIP was performed as previously described [30] using an antibody specific to Tra2b [65].”
BackgroundMethodCPEB1 mediates epithelial-to-mesenchyme transition and breast cancer metastasis
Nagaoka, K., Fujii, K., Zhang, H., Usuda, K., Watanabe, G., Ivshina, M. P., & Richter, J. D. (2015) · Oncogene · doi:10.1038/onc.2015.350 · Cited by 75
“39 Our results show that in vivo, reduced CPEB1 levels promote metastasis of breast cancer cells to the lung whereas ectopic expression of CPEB1 strongly inhibits it, suggesting that CPEB1 could be a good prognosticator of human breast cancer metastasis.”
Identification of RNA recognition elements in the Saccharomyces cerevisiae transcriptome
Riordan, D. P., Herschlag, D., & Brown, P. O. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq920 · Cited by 74
RIPiT-Seq: A high-throughput approach for footprinting RNA:protein complexes
Singh, G., Ricci, E. P., & Moore, M. J. (2013) · Methods · doi:10.1016/j.ymeth.2013.09.013 · Cited by 76
Ciesiołka, A., Jazurek, M., Drążkowska, K., & Krzyżosiak, W. J. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00097 · Cited by 74
“Last, in order to determine the exact protein-binding sites within repeat-containing transcripts, high-throughput technologies that exploit improved in vivo RIP analysis followed by NGS (CLIP-based methods) can be of use, i.e., CLIP (Ule et al., 2005; Jensen and Darnell, 2008), HiTS-CLIP (Licatalosi et al., 2008; Zhan…”
MethodHwang, H.-W., Saito, Y., Park, C. Y., Blachère, N. E., Tajima, Y., Fak, J. J., Zucker-Scharff, I., & Darnell, R. B. (2017) · Neuron · doi:10.1016/j.neuron.2017.08.024 · Cited by 74
Self-citationDiscovery of physiological and cancer-related regulators of 3′ UTR processing with KAPAC
Gruber, A. J., Schmidt, R., Ghosh, S., Martin, G., Gruber, A. J., van Nimwegen, E., & Zavolan, M. (2018) · Genome biology · doi:10.1186/s13059-018-1415-3 · Cited by 75
“Other splicing factors that have been linked to poly(A) site selection are the neuron-specific NOVA1 protein [20], the nuclear and cytoplasmic poly(A) binding proteins [12, 21], the heterogeneous ribo-nucleoprotein K (HNRNPK) [22], and the poly(C) binding protein (PCBP1) [23].”
BackgroundSecondary structures in RNA synthesis, splicing and translation
Georgakopoulos‐Soares, I., Parada, G. E., & Hemberg, M. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.05.041 · Cited by 79
“Cross-linking immunoprecipitation high-throughput sequencing (CLIP-seq) enables the investigation of protein interactions with RNA molecules [12] from which many variant technologies have emerged.”
BackgroundMeans to an end: mechanisms of alternative polyadenylation of messenger RNA precursors
Gruber, A. R., Martin, G., Keller, W., & Zavolan, M. (2013) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1206 · Cited by 78
Calarco, J. A., Zhen, M., & Blencowe, B. J. (2011) · RNA · doi:10.1261/rna.2603911 · Cited by 72
Feng, H., Moakley, D. F., Chen, S., McKenzie, M. G., Menon, V., & Zhang, C. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2013056118 · Cited by 76
Functional Analysis of Long Noncoding RNAs in Development and Disease
Chen, L., & Zhao, J. C. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-1221-6_4 · Cited by 72
“…including to identify splicing factor recognition sites, such as the RNA networks of splicing factor NOVA in mouse brain tissue (Ule et al. 2003 ; Licatalosi et al. 2008 ; Zhang et al. 2010 ), FOX2 binding sites in stem cells (Yeo et al. 2009 ), and SFRS1 interaction sites (Sanford et al. 2009 )…”
BackgroundHwang, H., Park, C. Y., Goodarzi, H., Fak, J. J., Mele, A., Moore, M. J., Saito, Y., & Darnell, R. B. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.023 · Cited by 72
“CLIP captures direct RNA-protein interaction in situ, allowing stringent immunopurification that effectively eliminates nonspecific interactions to generate precise genome-wide interaction maps (Licatalosi et al., 2008).”
BackgroundResultSelf-citationRay, D., Ha, K., Nie, K., Zheng, H., Hughes, T. R., & Morris, Q. (2016) · Methods · doi:10.1016/j.ymeth.2016.12.003 · Cited by 68
“Iterative washing removes unbound RNA whereas bound RNAs are eluted, purified, directly labeled with either Cy3 or Cy5, and hybridized to Agilent custom 244K arrays.”
InfluentialGenome-wide methods for investigating long noncoding RNAs
Cao, M., Zhao, J., & Hu, G. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.12.078 · Cited by 70
“suggesting the role of Nova in regulating alternative polyadenylation in the brain [23].”
BackgroundMethodSplicing factors: Insights into their regulatory network in alternative splicing in cancer
Du, J.-X., Zhu, G., Cai, J., Wang, B., Luo, Y., Chen, C., Cai, C.-Z., Zhang, S., Zhou, J., Fan, J., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.11.043 · Cited by 72
Cunliffe, V. T., Baines, R., Giachello, C. N., Lin, W., Morgan, A., Reuber, M., Russell, C., Walker, M. C., & Williams, R. S. B. (2014) · Seizure · doi:10.1016/j.seizure.2014.09.018 · Cited by 74
Teplova, M., Malinina, L. V., Darnell, J. C., Song, J., Lu, M., Abagyan, R. A., Musunuru, K., Теплов, А. А., Burley, S. K., Darnell, R. B., et al. (2011) · Structure · doi:10.1016/j.str.2011.05.002 · Cited by 71
“Full-length Nova proteins containing three KH domains have beenshown to targetand regulatealternativesplicingeventswithin neuronal pre-mRNAs that contain repeats of the (YCAY) binding element (Buckanovich and Darnell, 1997; Dredge and Darnell, 2003; Dredge et al., 2005; Licatalosi et al., 2008; Ule et al., 2006; Zhang…”
InfluentialSelf-citationPlant polyadenylation factors: conservation and variety in the polyadenylation complex in plants
Hunt, A. G., Xing, D., & Li, Q. Q. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-641 · Cited by 78
“In genes that possess multiple sites, different patterns of poly(A) site choice are seen in different tissues and different development stages, indicating that APA may be regulated by developmental or environmental cues [9,11,18-20].”
BackgroundPost‐transcriptional regulation in corticogenesis: how RNA‐binding proteins help build the brain
Pilaz, L., & Silver, D. L. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1289 · Cited by 72
An alternative splicing program promotes adipose tissue thermogenesis
Vernia, S., Edwards, Y. J. K., Han, M. S., Cavanagh, J., Barrett, T., Kim, J. K., & Davis, R. J. (2016) · eLife · doi:10.7554/elife.17672 · Cited by 71
Data Science Issues in Studying Protein–RNA Interactions with CLIP Technologies
Chakrabarti, A. M., Haberman, N., Praznik, A., Luscombe, N. M., & Ule, J. (2018) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-080917-013525 · Cited by 71
Self-citationThe “Observer Effect” in Genome-wide Surveys of Protein-RNA Interactions
Riley, K. J.-L., & STEITZ, J. A. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.030 · Cited by 70
“The addition of high-throughput sequencing of crosslinked RNA fragments (HITS-CLIP) permits genome-scale identification of direct RNA targets, largely overcomes the issue of UV crosslinking inefficiency (Licatalosi et al., 2008), and exhibits good reproducibility between biological replicates (for example, R(2) > 0.”
BackgroundInfluentialThe neuronal splicing factor Nova co-localizes with target RNAs in the dendrite
Racca, C. (2010) · Frontiers in Neural Circuits · doi:10.3389/neuro.04.005.2010 · Cited by 69
Prediction of RNA–protein interactions using a nucleotide language model
Yamada, K., & Hamada, M. (2022) · Bioinformatics Advances · doi:10.1093/bioadv/vbac023 · Cited by 70
Tissue‐specific mechanisms of alternative polyadenylation: testis, brain, and beyond
MacDonald, C. C., & McMahon, K. W. (2010) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.29 · Cited by 68
Gazina, E. V., Richards, K. L., Mokhtar, M. B. C., Thomas, E. A., Reid, C. A., & Petrou, S. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.011 · Cited by 63
Prediction of clustered RNA-binding protein motif sites in the mammalian genome
Zhang, C., Lee, K., Swanson, M. S., & Darnell, R. B. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt421 · Cited by 65
“Combined with high-throughput sequencing (HITS-CLIP), this approach is able to map in vivo protein–RNA interactions at a genome-wide scale (30,31).”
BackgroundMethodSelf-citationApplications of deep learning in understanding gene regulation
Li, Z., Gao, E., Zhou, J., Han, W., Xu, X., & Gao, X. (2023) · Cell Reports Methods · doi:10.1016/j.crmeth.2022.100384 · Cited by 73
“…such as chromatin immunoprecipitation sequencing (ChIP-seq) 1 for protein-DNA binding, cross-linking immunoprecipitation sequencing (CLIP-seq) 2,3 for protein-RNA binding, DNase I hypersensitive sites sequencing (DNase-seq) 4 and assay for transposase-accessible chromatin using sequencing…”
MethodHITS-CLIP reveals key regulators of nuclear receptor signaling in breast cancer
Pillai, M. M., Gillen, A. E., Yamamoto, T. M., Kline, E. C., Brown, J., Flory, K., Hesselberth, J. R., & Kabos, P. (2014) · Breast Cancer Research and Treatment · doi:10.1007/s10549-014-3004-9 · Cited by 69
Inhibition of Non-ATG Translational Events in Cells via Covalent Small Molecules Targeting RNA
Yang, W., Wilson, H. D., Velagapudi, S. P., & Disney, M. D. (2015) · Journal of the American Chemical Society · doi:10.1021/ja507448y · Cited by 68
Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders
Smith, R. M., & Sadée, W. (2011) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2011.00001 · Cited by 70
“Methods such as UV-based protein-RNA crosslinking, coupled with ultra high-throughput sequencing (Licatalosi et al., 2008) are available to begin answering these questions. dIScuSSIon Identifying novel ASD risk genes remains an ongoing endeavor.”
RNA-Binding Proteins in Regulation of Alternative Cleavage and Polyadenylation
Zheng, D., & Tian, B. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-1221-6_3 · Cited by 66
A survey of software for genome-wide discovery of differential splicing in RNA-Seq data
Hooper, J. E. (2014) · Human Genomics · doi:10.1186/1479-7364-8-3 · Cited by 67
“Exon junction microarrays (Affymetrix HJAY or MJAY arrays, Santa Clara, CA, USA [46]) offer an oft-overlooked approach with higher sensitivity than RNA-Seq for well-annotated alternative splices.”
BackgroundThe landscape of alternative polyadenylation in single cells of the developing mouse embryo
Agarwal, V., Lopez-Darwin, S. L., Kelley, D. R., & Shendure, J. (2021) · Nature Communications · doi:10.1038/s41467-021-25388-8 · Cited by 66
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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