Vasileiou G, Ekici AB, Urebe S, Zweier C, Hoyer J, Engels H, Behrens J, Reis A, Hadjihannas M (2015)
Publication Type: Journal article
Publication year: 2015
Book Volume: 97
Pages Range: 445-56
Journal Issue: 3
DOI: 10.1016/j.ajhg.2015.08.002
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/?-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/?-catenin target genes are upregulated. Using cellular models of low and high Wnt/?-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/?-catenin target genes and Wnt/?-catenin-dependent transcriptional reporters in a ?-catenin-dependent manner. Reciprocally, forced expression of ARID1B inhibits Wnt/?-catenin signaling downstream of the ?-catenin destruction complex. Both endogenous and exogenous ARID1B associate with ?-catenin and repress Wnt/?-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 ?-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/?-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through ?-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/?-catenin signaling pathway.
APA:
Vasileiou, G., Ekici, A.B., Urebe, S., Zweier, C., Hoyer, J., Engels, H.,... Hadjihannas, M. (2015). Chromatin-Remodeling-Factor ARID1B Represses Wnt/?-Catenin Signaling. American Journal of Human Genetics, 97(3), 445-56. https://doi.org/10.1016/j.ajhg.2015.08.002
MLA:
Vasileiou, Georgia, et al. "Chromatin-Remodeling-Factor ARID1B Represses Wnt/?-Catenin Signaling." American Journal of Human Genetics 97.3 (2015): 445-56.
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