Zhang, C., Zhang, Z., Castle, J., Sun, S., Johnson, J., Krainer, A. R., Zhang, M. Q. (September 2008) Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes Dev, 22 (18). pp. 2550-63.
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Abstract
The precise regulation of many alternative splicing (AS) events by specific splicing factors is essential to determine tissue types and developmental stages. However, the molecular basis of tissue-specific AS regulation and the properties of splicing regulatory networks (SRNs) are poorly understood. Here we comprehensively predict the targets of the brain- and muscle-specific splicing factor Fox-1 (A2BP1) and its paralog Fox-2 (RBM9) and systematically define the corresponding SRNs genome-wide. Fox-1/2 are conserved from worm to human, and specifically recognize the RNA element UGCAUG. We integrate Fox-1/2-binding specificity with phylogenetic conservation, splicing microarray data, and additional computational and experimental characterization. We predict thousands of Fox-1/2 targets with conserved binding sites, at a false discovery rate (FDR) of approximately 24%, including many validated experimentally, suggesting a surprisingly extensive SRN. The preferred position of the binding sites differs according to AS pattern, and determines either activation or repression of exon recognition by Fox-1/2. Many predicted targets are important for neuromuscular functions, and have been implicated in several genetic diseases. We also identified instances of binding site creation or loss in different vertebrate lineages and human populations, which likely reflect fine-tuning of gene expression regulation during evolution.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Tissue-specific alternative splicing splicing regulatory network Fox-1/A2BP1 Fox-2/RBM9 UGCAUG comparative genomics |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor |
| CSHL Authors: | |
| Communities: | CSHL labs > Krainer lab CSHL labs > Zhang lab |
| Depositing User: | Matt Covey |
| Date: | 15 September 2008 |
| Date Deposited: | 26 Feb 2013 21:25 |
| Last Modified: | 03 Nov 2017 20:16 |
| PMCID: | PMC2546699 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27511 |
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