Chromatin-Remodeling-Factor ARID1B Represses Wnt/β-Catenin Signaling
Open accessAbstract
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.
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Mutations disrupting ARID1B result in activation of Wnt signaling and dysregulation of B-catenin transcription.
“Mutations that disrupt ARID1B result in activation of Wnt signaling and dysregulation of B-catenin transcription (Vasileiou et al., 2015).”
From Getting to the cores of autism (2019) · cites this paper as Vasileiou et al., 2015
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Getting to the cores of autism
Iakoucheva, L. M., Muotri, A. R., & Sebat, J. (2019) · Cell · doi:10.1016/j.cell.2019.07.037 · Cited by 260 · see citing works
“disruptARID1B result in activation of Wnt signaling and dysregulation of B-catenin transcription (Vasileiou et al., 2015).”
BackgroundNeocortical neurogenesis and the etiology of autism spectrum disorder
Packer, A. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.002 · Cited by 138 · see citing works
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- Authors
- Vasileiou, G., Ekici, A. B., Uebe, S., Zweier, C., Hoyer, J., Engels, H., Behrens, J., Reis, A., & Hadjihannas, M. V.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Bonn (DE)
- Corresponding author
- Reis, André
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 97
- Issue
- 3
- Pages
- 445-456
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4564991
- OpenAlex
- W1914281583
- Cited by
- 81
- References
- 49
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 9 · 2022: 6 · 2021: 15 · 2020: 9 · 2019: 8 · 2018: 10 · 2017: 4 · 2016: 6 · 2015: 2
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- ARID1B, Wnt/β-catenin signaling, chromatin remodeling, SWI/SNF complex, SMARCA4, transcriptional repression, intellectual disability, cancer, β-catenin destruction complex, neurite outgrowth, brain development, loss-of-function mutations
- MeSH terms
- DNA-Binding Proteins, Humans, Luciferases, Microscopy, Fluorescence, Transcription Factors, Blotting, Western, DNA, Complementary, Computational Biology, RNA, Small Interfering, Chromatin Assembly and Disassembly, Immunoprecipitation, beta Catenin, Wnt Signaling Pathway, Real-Time Polymerase Chain Reaction
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