Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 329 (5990): 439-443

Copyright © 2010 by the American Association for the Advancement of Science

Integrative Modeling Defines the Nova Splicing-Regulatory Network and Its Combinatorial Controls

Chaolin Zhang,* Maria A. Frias, Aldo Mele, Matteo Ruggiu, Taesun Eom, Christina B. Marney, Huidong Wang, Donny D. Licatalosi, John J. Fak, Robert B. Darnell*

Abstract: The control of RNA alternative splicing is critical for generating biological diversity. Despite emerging genome-wide technologies to study RNA complexity, reliable and comprehensive RNA-regulatory networks have not been defined. Here, we used Bayesian networks to probabilistically model diverse data sets and predict the target networks of specific regulators. We applied this strategy to identify ~700 alternative splicing events directly regulated by the neuron-specific factor Nova in the mouse brain, integrating RNA-binding data, splicing microarray data, Nova-binding motifs, and evolutionary signatures. The resulting integrative network revealed combinatorial regulation by Nova and the neuronal splicing factor Fox, interplay between phosphorylation and splicing, and potential links to neurologic disease. Thus, we have developed a general approach to understanding mammalian RNA regulation at the systems level.

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

* To whom correspondence should be addressed. E-mail: czhang{at}rockefeller.edu (C.Z.); darnelr{at}rockefeller.edu (R.B.D.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy.
F. Rusconi, L. Paganini, D. Braida, L. Ponzoni, E. Toffolo, A. Maroli, N. Landsberger, F. Bedogni, E. Turco, L. Pattini, et al. (2014)
Cereb Cortex
   Abstract »    Full Text »    PDF »
Tumor microenvironment-associated modifications of alternative splicing.
J.-P. Brosseau, J.-F. Lucier, H. Nwilati, P. Thibault, D. Garneau, D. Gendron, M. Durand, S. Couture, E. Lapointe, P. Prinos, et al. (2014)
RNA 20, 189-201
   Abstract »    Full Text »    PDF »
Modeling the binding specificity of the RNA-binding protein GLD-1 suggests a function of coding region-located sites in translational repression.
A. Brummer, S. Kishore, D. Subasic, M. Hengartner, and M. Zavolan (2013)
RNA 19, 1317-1326
   Abstract »    Full Text »    PDF »
Complexity of the Alternative Splicing Landscape in Plants.
A. S. N. Reddy, Y. Marquez, M. Kalyna, and A. Barta (2013)
PLANT CELL 25, 3657-3683
   Abstract »    Full Text »    PDF »
Prediction of clustered RNA-binding protein motif sites in the mammalian genome.
C. Zhang, K.-Y. Lee, M. S. Swanson, and R. B. Darnell (2013)
Nucleic Acids Res. 41, 6793-6807
   Abstract »    Full Text »    PDF »
OLego: fast and sensitive mapping of spliced mRNA-Seq reads using small seeds.
J. Wu, O. Anczukow, A. R. Krainer, M. Q. Zhang, and C. Zhang (2013)
Nucleic Acids Res. 41, 5149-5163
   Abstract »    Full Text »    PDF »
Reflections on the history of pre-mRNA processing and highlights of current knowledge: A unified picture.
J. E. Darnell Jr. (2013)
RNA 19, 443-460
   Abstract »    Full Text »    PDF »
Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development.
K. K. Kim, J. Nam, Y.-s. Mukouyama, and S. Kawamoto (2013)
J. Cell Biol. 200, 443-458
   Abstract »    Full Text »    PDF »
RBFOX2 Is an Important Regulator of Mesenchymal Tissue-Specific Splicing in both Normal and Cancer Tissues.
J. P. Venables, J.-P. Brosseau, G. Gadea, R. Klinck, P. Prinos, J.-F. Beaulieu, E. Lapointe, M. Durand, P. Thibault, K. Tremblay, et al. (2013)
Mol. Cell. Biol. 33, 396-405
   Abstract »    Full Text »    PDF »
NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure.
T. Eom, C. Zhang, H. Wang, K. Lay, J. Fak, J. L. Noebels, and R. B. Darnell (2013)
eLife Sci 2, e00178
   Abstract »    Full Text »    PDF »
Dynamic Expression Pattern of Neuro-oncological Ventral Antigen 1 (Nova1) in the Rat Brain after Focal Cerebral Ischemia/Reperfusion Insults.
H. Li, C. Sun, Y. Wang, Y. Gao, Y. Liu, Y. Gao, X. Li, and C. Zhang (2013)
Journal of Histochemistry & Cytochemistry 61, 45-54
   Abstract »    Full Text »    PDF »
Alternative polyadenylation: New insights from global analyses.
Y. Shi (2012)
RNA 18, 2105-2117
   Abstract »    Full Text »    PDF »
Site identification in high-throughput RNA-protein interaction data.
P. J. Uren, E. Bahrami-Samani, S. C. Burns, M. Qiao, F. V. Karginov, E. Hodges, G. J. Hannon, J. R. Sanford, L. O. F. Penalva, and A. D. Smith (2012)
Bioinformatics 28, 3013-3020
   Abstract »    Full Text »    PDF »
RBFOX1 regulates both splicing and transcriptional networks in human neuronal development.
B. L. Fogel, E. Wexler, A. Wahnich, T. Friedrich, C. Vijayendran, F. Gao, N. Parikshak, G. Konopka, and D. H. Geschwind (2012)
Hum. Mol. Genet. 21, 4171-4186
   Abstract »    Full Text »    PDF »
Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice.
A. Berson, S. Barbash, G. Shaltiel, Y. Goll, G. Hanin, D. S. Greenberg, M. Ketzef, A. J. Becker, A. Friedman, and H. Soreq (2012)
EMBO Mol Med. 4, 730-742
   Abstract »    Full Text »    PDF »
Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain.
D. D. Licatalosi, M. Yano, J. J. Fak, A. Mele, S. E. Grabinski, C. Zhang, and R. B. Darnell (2012)
Genes & Dev. 26, 1626-1642
   Abstract »    Full Text »    PDF »
RIP-chip-SRM--a new combinatorial large-scale approach identifies a set of translationally regulated bantam/miR-58 targets in C. elegans.
M. Jovanovic, L. Reiter, A. Clark, M. Weiss, P. Picotti, H. Rehrauer, A. Frei, L. J. Neukomm, E. Kaufman, B. Wollscheid, et al. (2012)
Genome Res. 22, 1360-1371
   Abstract »    Full Text »    PDF »
Genome-Wide Determination of a Broad ESRP-Regulated Posttranscriptional Network by High-Throughput Sequencing.
K. A. Dittmar, P. Jiang, J. W. Park, K. Amirikian, J. Wan, S. Shen, Y. Xing, and R. P. Carstens (2012)
Mol. Cell. Biol. 32, 1468-1482
   Abstract »    Full Text »    PDF »
Spatial arrangement of an RNA zipcode identifies mRNAs under post-transcriptional control.
V. L. Patel, S. Mitra, R. Harris, A. R. Buxbaum, T. Lionnet, M. Brenowitz, M. Girvin, M. Levy, S. C. Almo, R. H. Singer, et al. (2012)
Genes & Dev. 26, 43-53
   Abstract »    Full Text »    PDF »
Analysis of alternative splicing associated with aging and neurodegeneration in the human brain.
J. R. Tollervey, Z. Wang, T. Hortobagyi, J. T. Witten, K. Zarnack, M. Kayikci, T. A. Clark, A. C. Schweitzer, G. Rot, T. Curk, et al. (2011)
Genome Res. 21, 1572-1582
   Abstract »    Full Text »    PDF »
Bayesian prediction of tissue-regulated splicing using RNA sequence and cellular context.
H. Y. Xiong, Y. Barash, and B. J. Frey (2011)
Bioinformatics 27, 2554-2562
   Abstract »    Full Text »    PDF »
Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts.
J. A. Calarco, M. Zhen, and B. J. Blencowe (2011)
RNA 17, 775-791
   Abstract »    Full Text »    PDF »
Stepwise assembly of the Nova-regulated alternative splicing network in the vertebrate brain.
M. Irimia, A. Denuc, D. Burguera, I. Somorjai, J. M. Martin-Duran, G. Genikhovich, S. Jimenez-Delgado, U. Technau, S. W. Roy, G. Marfany, et al. (2011)
PNAS 108, 5319-5324
   Abstract »    Full Text »    PDF »
Conservation of an RNA regulatory map between Drosophila and mammals.
A. N. Brooks, L. Yang, M. O. Duff, K. D. Hansen, J. W. Park, S. Dudoit, S. E. Brenner, and B. R. Graveley (2011)
Genome Res. 21, 193-202
   Abstract »    Full Text »    PDF »
Global Profiling and Molecular Characterization of Alternative Splicing Events Misregulated in Lung Cancer.
C. M. Misquitta-Ali, E. Cheng, D. O'Hanlon, N. Liu, C. J. McGlade, M. S. Tsao, and B. J. Blencowe (2011)
Mol. Cell. Biol. 31, 138-150
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882