Title | HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | 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 |
Journal | Cell Rep |
Volume | 6 |
Issue | 6 |
Pagination | 1139-1152 |
Date Published | 2014 Mar 27 |
ISSN | 2211-1247 |
Keywords | Alternative Splicing, Animals, Autistic Disorder, Base Sequence, Brain, Exons, Gene Regulatory Networks, Genetic Predisposition to Disease, Humans, Immunoprecipitation, Mice, Models, Genetic, Models, Molecular, Molecular Sequence Data, Repressor Proteins, RNA, RNA-Binding Proteins |
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. |
DOI | 10.1016/j.celrep.2014.02.005 |
Alternate Journal | Cell Rep |
PubMed ID | 24613350 |
PubMed Central ID | PMC3992522 |
Grant List | R00GM95713 / GM / NIGMS NIH HHS / United States HG001696 / HG / NHGRI NIH HHS / United States R01 NS081706 / NS / NINDS NIH HHS / United States R37 GM042699 / GM / NIGMS NIH HHS / United States R00 GM095713 / GM / NIGMS NIH HHS / United States GM74688 / GM / NIGMS NIH HHS / United States R01 NS034389 / NS / NINDS NIH HHS / United States R01 GM074688 / GM / NIGMS NIH HHS / United States R56 NS034389 / NS / NINDS NIH HHS / United States / / Howard Hughes Medical Institute / United States P30 CA045508 / CA / NCI NIH HHS / United States GM42699 / GM / NIGMS NIH HHS / United States R01 HG001696 / HG / NHGRI NIH HHS / United States NS34389 / NS / NINDS NIH HHS / United States NS81706 / NS / NINDS NIH HHS / United States |
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