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Cell Rep. 2014 Mar 27;6(6):1139-52. doi: 10.1016/j.celrep.2014.02.005. Epub 2014 Mar 6.

HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism.

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  • 1Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
  • 2Howard Hughes Medical Institute, Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, NY 10065, USA.
  • 3Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
  • 4Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • 6Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 7Department of Molecular and Cell Biology, Center for Systems Biology, The University of Texas at Dallas, Richardson, TX 75080, USA; Bioinformatics Division, Center for Synthetic and Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China.
  • 8Howard Hughes Medical Institute, Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, NY 10065, USA. Electronic address: darnelr@rockefeller.edu.
  • 9Department of Systems Biology, Department of Biochemistry and Molecular Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA. Electronic address: cz2294@columbia.edu.

Abstract

The RNA binding proteins Rbfox1/2/3 regulate alternative splicing in the nervous system, and disruption of Rbfox1 has been implicated in autism. However, comprehensive identification of functional Rbfox targets has been challenging. Here, we perform HITS-CLIP for all three Rbfox family members in order to globally map, at a single-nucleotide resolution, their in vivo RNA interaction sites in the mouse brain. We find that the two guanines in the Rbfox binding motif UGCAUG are critical for protein-RNA interactions and crosslinking. Using integrative modeling, these interaction sites, combined with additional datasets, define 1,059 direct Rbfox target alternative splicing events. Over half of the quantifiable targets show dynamic changes during brain development. Of particular interest are 111 events from 48 candidate autism-susceptibility genes, including syndromic autism genes Shank3, Cacna1c, and Tsc2. Alteration of Rbfox targets in some autistic brains is correlated with downregulation of all three Rbfox proteins, supporting the potential clinical relevance of the splicing-regulatory network.

PMID:
24613350
PMCID:
PMC3992522
DOI:
10.1016/j.celrep.2014.02.005
[PubMed - indexed for MEDLINE]
Free PMC Article
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