Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 97, Issue 3, Pages 445-456Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2015.08.002
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Funding
- German Intellectual Disability Network (MRNET) from the German Ministry of Education and Research [01GS08160]
- Interdisciplinary Center for Clinical Research Erlangen [E16]
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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/beta-catenin signaling. Through whole-transcriptome analysis, we find that in individuals with intellectual disability and ARID1B loss-of-function mutations, Wnt/beta-catenin target genes are upregulated. Using cellular models of low and high Wnt/beta-catenin activity, we demonstrate that knockdown of ARID1B activates Wnt/beta-catenin target genes and Wnt/beta-catenin-dependent transcriptional reporters in a beta-catenin-dependent manner. Reciprocally, forced expression of ARID 1B inhibits Wnt/beta-catenin signaling downstream of the beta-catenin destruction complex. Both endogenous and exogenous ARID1B associate with beta-catenin and repress Wnt/beta-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 P-catenin, and the resultant ARID1B mutant proteins fail to suppress Wnt/beta-catenin signaling. Finally, knockdown of ARID1B in mouse neuroblastoma cells leads to neurite outgrowth through beta-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/beta-catenin signaling pathway.
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