Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution
Open accessAbstract
High-throughput sequencing-based methods and their applications in the study of transcriptomes have revolutionized our understanding of alternative splicing. Networks of functionally coordinated and biologically important alternative splicing events continue to be discovered in an ever-increasing diversity of cell types in the context of physiologically normal and disease states. These studies have been complemented by efforts directed at defining sequence codes governing splicing and their cognate trans-acting factors, which have illuminated important combinatorial principles of regulation. Additional studies have revealed critical roles of position-dependent, multivalent protein-RNA interactions that direct splicing outcomes. Investigations of evolutionary changes in RNA binding proteins, splice variants, and associated cis elements have further shed light on the emergence, mechanisms, and functions of splicing networks. Progress in these areas has emphasized the need for a coordinated, community-based effort to systematically address the functions of individual splice variants associated with normal and disease biology.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Similar position-dependent RNA regulatory maps have been reported for other splicing regulators, which function in a cell type- or condition-specific manner.
“Similar position-dependent RNA regulatory maps have been reported for other splicing regulators, which function in a cell type- or condition-specific manner (Ule and Blencowe 2019).”
From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Ule and Blencowe 2019
Cites
HITS-CLIP yields genome-wide insights into brain alternative RNA processing
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., et al. (2008) · Nature · doi:10.1038/nature07488 · Cited by 1,352 · cited 1× · see citing works
“Initially, studies of Nova proteins revealed RNA maps accounting for their dual effects on splicing in the brain that depend on their binding position on pre-mRNA, defined either by analysis of multivalent motifs or with CLIP data (Licatalosi et al., 2008; Ule et al., 2006).”
BackgroundSelf-citationA large-scale binding and functional map of human RNA-binding proteins
Van Nostrand, E. L., Freese, P., Pratt, G. A., Wang, X., Wei, X., Xiao, R., Blue, S. M., Chen, J.-Y., Cody, N. A. L., Dominguez, D., et al. (2020) · Nature · doi:10.1038/s41586-020-2077-3 · Cited by 1,317 · see citing works
CLIP Identifies Nova-Regulated RNA Networks in the Brain
Ule, J., Jensen, K. B., Ruggiu, M., Mele, A., Ule, A., & Darnell, R. B. (2003) · Science · doi:10.1126/science.1090095 · Cited by 1,120 · see citing works
Self-citationContext-dependent control of alternative splicing by RNA-binding proteins
Fu, X.-D., & Ares, M. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3778 · Cited by 1,044 · see citing works
Function of alternative splicing
Kelemen, O., Convertini, P., Zhang, Z., Wen, Y., Shen, M., Falaleeva, M., & Stamm, S. (2013) · Gene · doi:10.1016/j.gene.2012.07.083 · Cited by 743 · see citing works
A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains
Irimia, M., Weatheritt, R. J., Ellis, J. D., Parikshak, N. N., Gonatopoulos-Pournatzis, T., Babor, M., Quesnel-Vallières, M., Tapial, J., Raj, B., O’Hanlon, D., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.035 · Cited by 693 · cited 5× · see citing works
“In contrast to longer neurally regulated exons that are enriched within IDRs, as described above, neural microexons significantly overlap or are adjacent to modular domains that function in mediating protein and other ligand interactions (Irimia et al., 2014).”
BackgroundInfluentialSelf-citationXue, Y., Zhou, Y., Wu, T., Zhu, T., Ji, X., Kwon, Y.-S., Zhang, C., Yeo, G., Black, D. L., Sun, H., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.12.003 · Cited by 469 · see citing works
Buljan, M., Chalancon, G., Eustermann, S., Wagner, G. P., Fuxreiter, M., Bateman, A., & Babu, M. M. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.039 · Cited by 396 · see citing works
Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia
Wang, E., Lu, S. X., Pastore, A., Chen, X., Imig, J., Chun-Wei Lee, S., Hockemeyer, K., Ghebrechristos, Y. E., Yoshimi, A., Inoue, D., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.01.010 · Cited by 338 · see citing works
Llorian, M., Schwartz, S., Clark, T. A., Hollander, D., Tan, L.-Y., Spellman, R., Gordon, A., Schweitzer, A. C., de la Grange, P., Ast, G., et al. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1881 · Cited by 263 · see citing works
The Relationship between Alternative Splicing and Proteomic Complexity
Blencowe, B. J. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.04.001 · Cited by 178 · see citing works
Self-citationQuesnel-Vallières, M., Dargaei, Z., Irimia, M., Gonatopoulos-Pournatzis, T., Ip, J. Y., Wu, M., Sterne-Weiler, T., Nakagawa, S., Woodin, M. A., Blencowe, B. J., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.11.033 · Cited by 178 · see citing works
Self-citationThe ribosome-engaged landscape of alternative splicing
Weatheritt, R. J., Sterne-Weiler, T., & Blencowe, B. J. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3317 · Cited by 162 · see citing works
Self-citationAn alternative splicing event amplifies evolutionary differences between vertebrates
Gueroussov, S., Gonatopoulos-Pournatzis, T., Irimia, M., Raj, B., Lin, Z.-Y., Gingras, A.-C., & Blencowe, B. J. (2015) · Science · doi:10.1126/science.aaa8381 · Cited by 148 · see citing works
Self-citationBuilding Robust Transcriptomes with Master Splicing Factors
Jangi, M., & Sharp, P. A. (2014) · Cell · doi:10.1016/j.cell.2014.09.054 · Cited by 141 · see citing works
A Global Regulatory Mechanism for Activating an Exon Network Required for Neurogenesis
Raj, B., Irimia, M., Braunschweig, U., Sterne-Weiler, T., O’Hanlon, D., Lin, Z.-Y., Chen, G. I., Easton, L. E., Ule, J., Gingras, A.-C., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.011 · Cited by 132 · cited 5× · see citing works
“It is intriguing that RNPS1, an auxiliary EJC component, can repress inclusion of such cryptic microexons, whereas, on the other hand, it promotes splicing of canonical neural microexons (Gonatopoulos-Pournatzis et al., 2018).”
BackgroundInfluentialSelf-citationFunctional coordination of alternative splicing in the mammalian central nervous system
Fagnani, M., Barash, Y., Ip, J. Y., Misquitta, C., Pan, Q., Saltzman, A. L., Shai, O., Lee, L., Rozenhek, A., Mohammad, N., et al. (2007) · Genome Biology · doi:10.1186/gb-2007-8-6-r108 · Cited by 120 · see citing works
Self-citationNOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure
Eom, T., Zhang, C., Wang, H., Lay, K., Fak, J., Noebels, J. L., & Darnell, R. B. (2013) · eLife · doi:10.7554/elife.00178 · Cited by 118 · see citing works
Wang, X., Codreanu, S. G., Wen, B., Li, K., Chambers, M. C., Liebler, D. C., & Zhang, B. (2018) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000155 · Cited by 97 · cited 1× · see citing works
“, based on an in silico analysis) to miss detection of the majority of splice junction-spanning peptides (Wang et al., 2018), and mass spectrometry (MS) analysis methods, such as those employed by Tress et al.”
MethodA U1-U2 snRNP interaction network during intron definition
Shao, W., Kim, H.-S., Cao, Y., Xu, Y.-Z., & Query, C. C. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06234-11 · Cited by 85 · see citing works
Stepwise assembly of the <i>Nova</i> -regulated alternative splicing network in the vertebrate brain
Irimia, M., Denuc, A., Burguera, D., Somorjai, I., Martín-Durán, J. M., Genikhovich, G., Jimenez-Delgado, S., Technau, U., Roy, S. W., Marfany, G., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1012333108 · Cited by 47 · cited 1× · see citing works
“, 2012), in agreement with the conserved nature of the binding specificities of orthologous RBPs and their cognate cis-acting elements (Irimia et al., 2011; Jelen et al., 2007; Oddo et al., 2016; Solana et al., 2016).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation
Bangru, S., Chen, J., Baker, N., Das, D., Chembazhi, U. V., Derham, J. M., Chorghade, S., Arif, W., Alencastro, F., Duncan, A. W., et al. (2025) · Genes & Development · doi:10.1101/gad.352129.124 · Cited by 4 · see citing works
- Authors
- Ule, J., & Blencowe, B. J.
- Affiliations
- The Francis Crick Institute (GB)
- University of Toronto (CA)
- Corresponding author
- Ule, Jernej
- Blencowe, Benjamin J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 76
- Issue
- 2
- Pages
- 329-345
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2980949872
- Cited by
- 780
- References
- 21
- Citations by year
- 2026: 98 · 2025: 122 · 2024: 145 · 2023: 118 · 2022: 142 · 2021: 99 · 2020: 54 · 2019: 2
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- European Research Council
- Wellcome Trust
- Canadian Institutes of Health Research
- Simons Foundation
- Canada First Research Excellence Fund
- 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
- alternative splicing, splicing regulatory network, RNA-binding proteins, trans-acting splicing factors, RNA-protein interactions, cis-regulatory elements, splice variants, transcriptome, disease biology
- MeSH terms
- Humans, RNA-Binding Proteins, Alternative Splicing, Evolution, Molecular
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
