| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Zweier, Christiane Ekici, Arif B. Behrens, Jürgen Reis, André Vasileiou, Georgia Uebe, Steffen Hoyer, Juliane Engels, Hartmut Hadjihannas, Michel V. |
| Description |
Country affiliation: Germany Author Affiliation: Vasileiou G ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.); Ekici AB ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.); Uebe S ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.); Zweier C ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.); Hoyer J ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.); Engels H ( Institute of Human Genetics, University of Bonn, 53105 Bonn, Germany.); Behrens J ( Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.); Reis A ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: andre.reis@uk-erlangen.de.); Hadjihannas MV ( Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany) |
| Abstract |
The link of chromatin remodeling to both neurodevelopment and cancer has recently been highlighted by the identification of mutations affecting BAF chromatin-remodeling components, such as ARID1B, in individuals with intellectual disability and cancer. However, the underlying molecular mechanism(s) remains unknown. Here, we show that ARID1B is a repressor of Wnt/ß-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/ß-catenin target genes are upregulated. Using cellular models of low and high Wnt/ß-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/ß-catenin target genes and Wnt/ß-catenin-dependent transcriptional reporters in a ß-catenin-dependent manner. Reciprocally, forced expression of ARID1B inhibits Wnt/ß-catenin signaling downstream of the ß-catenin destruction complex. Both endogenous and exogenous ARID1B associate with ß-catenin and repress Wnt/ß-catenin-mediated transcription through the BAF core subunit BRG1. Accordingly, mutations in ARID1B leading to partial or complete deletion of its BRG1-binding domain, as is often observed in intellectual disability and cancers, compromise association with ß-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/ß-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through ß-catenin. The data suggest that aberrations in chromatin-remodeling factors, such as ARID1B, might contribute to neurodevelopmental abnormalities and cancer through deregulation of developmental and oncogenic pathways, such as the Wnt/ß-catenin signaling pathway. |
| ISSN |
00029297 |
| e-ISSN |
15376605 |
| DOI |
10.1016/j.ajhg.2015.08.002 |
| Journal |
The American Journal of Human Genetics |
| Issue Number |
3 |
| Volume Number |
97 |
| Language |
English |
| Publisher |
Cell Press (on behalf of American Society of Human Genetics) |
| Publisher Date |
2015-09-03 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Chromatin Assembly And Disassembly Genetics Dna-binding Proteins Transcription Factors Wnt Signaling Pathway Beta Catenin Metabolism Blotting, Western Computational Biology Dna, Complementary Biosynthesis Immunoprecipitation Luciferases Microscopy, Fluorescence Rna, Small Interfering Real-time Polymerase Chain Reaction Research Support, Non-u.s. Gov't Discipline Human Genetics |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Genetics Genetics (clinical) |
