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Am J Hum Genet. 2015 Sep 3;97(3):445-56. doi: 10.1016/j.ajhg.2015.08.002.

Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling.

Author information

1
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
2
Institute of Human Genetics, University of Bonn, 53105 Bonn, Germany.
3
Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
4
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: andre.reis@uk-erlangen.de.
5
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Nikolaus-Fiebiger-Center for Molecular Medicine, 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/β-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/β-catenin target genes are upregulated. Using cellular models of low and high Wnt/β-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/β-catenin target genes and Wnt/β-catenin-dependent transcriptional reporters in a β-catenin-dependent manner. Reciprocally, forced expression of ARID1B inhibits Wnt/β-catenin signaling downstream of the β-catenin destruction complex. Both endogenous and exogenous ARID1B associate with β-catenin and repress Wnt/β-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 β-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/β-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through β-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/β-catenin signaling pathway.

PMID:
26340334
PMCID:
PMC4564991
DOI:
10.1016/j.ajhg.2015.08.002
[Indexed for MEDLINE]
Free PMC Article

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