Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling.
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.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Georgia
G
Vasileiou
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Arif B
AB
Ekici
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Steffen
S
Uebe
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Christiane
C
Zweier
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Juliane
J
Hoyer
Institute of Human Genetics, University of Bonn, 53105 Bonn, Germany.
Hartmut
H
Engels
Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Jürgen
J
Behrens
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: andre.reis@uk-erlangen.de.
André
A
Reis
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.
Michel V
MV
Hadjihannas
D015153:Blotting, Western; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D019295:Computational Biology; D018076:DNA, Complementary / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*
C497837:ARID1B protein, human; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051176:beta Catenin; D008156:Luciferases