HITS-CLIP and Integrative Modeling Define the Rbfox Splicing-Regulatory Network Linked to Brain Development and Autism

Sebastien M. Weyn-Vanhentenryck, Aldo Mele, Qinghong Yan, Shuying Sun, Natalie Farny, Zuo Zhang, Chenghai Xue, Margaret Herre, Pamela A. Silver, Michael Q. Zhang, Adrian R. Krainer, Robert B. Darnell, Chaolin Zhang

Research output: Contribution to journalArticle

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 invivo 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 targetalternative 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.

Original languageEnglish (US)
Pages (from-to)1139-1152
Number of pages14
JournalCell Reports
Volume6
Issue number6
DOIs
StatePublished - Mar 27 2014
Externally publishedYes

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Autistic Disorder
Brain
Genes
RNA
RNA-Binding Proteins
Alternative Splicing
Guanine
Neurology
Crosslinking
Nervous System
Proteins
Down-Regulation
Nucleotides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

HITS-CLIP and Integrative Modeling Define the Rbfox Splicing-Regulatory Network Linked to Brain Development and Autism. / Weyn-Vanhentenryck, Sebastien M.; Mele, Aldo; Yan, Qinghong; Sun, Shuying; Farny, Natalie; Zhang, Zuo; Xue, Chenghai; Herre, Margaret; Silver, Pamela A.; Zhang, Michael Q.; Krainer, Adrian R.; Darnell, Robert B.; Zhang, Chaolin.

In: Cell Reports, Vol. 6, No. 6, 27.03.2014, p. 1139-1152.

Research output: Contribution to journalArticle

Weyn-Vanhentenryck, SM, Mele, A, Yan, Q, Sun, S, Farny, N, Zhang, Z, Xue, C, Herre, M, Silver, PA, Zhang, MQ, Krainer, AR, Darnell, RB & Zhang, C 2014, 'HITS-CLIP and Integrative Modeling Define the Rbfox Splicing-Regulatory Network Linked to Brain Development and Autism', Cell Reports, vol. 6, no. 6, pp. 1139-1152. https://doi.org/10.1016/j.celrep.2014.02.005
Weyn-Vanhentenryck, Sebastien M. ; Mele, Aldo ; Yan, Qinghong ; Sun, Shuying ; Farny, Natalie ; Zhang, Zuo ; Xue, Chenghai ; Herre, Margaret ; Silver, Pamela A. ; Zhang, Michael Q. ; Krainer, Adrian R. ; Darnell, Robert B. ; Zhang, Chaolin. / HITS-CLIP and Integrative Modeling Define the Rbfox Splicing-Regulatory Network Linked to Brain Development and Autism. In: Cell Reports. 2014 ; Vol. 6, No. 6. pp. 1139-1152.
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