Chromatin-Remodeling-Factor ARID1B Represses Wnt/?-Catenin Signaling

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

Journal

American Journal of Human Genetics Elsevier (Cell Press)

Book Volume: 97

Pages Range: 445-56

Journal Issue: 3

DOI: 10.1016/j.ajhg.2015.08.002

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/?-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.

Authors with CRIS profile

Arif Bülent Ekici Institute of Human Genetics Christiane Zweier Medizinische Fakultät Juliane Hoyer Institute of Human Genetics Jürgen Behrens Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Michel Hadjihannas Institute of Human Genetics

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

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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