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

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/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.

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

“…The differentiation state of individual cells in spheres and/or different levels of shRNA expression after lentiviral infection may account for this variation. While our study was nearing completion, Vasileiou et al (2015) showed that, as in our study, reducing ARID1B increases Wnt/β-catenin target gene expression. They also overexpressed ARID1B by transient transfection and inhibited Wnt/β-catenin activity in cell lines.…”

“…Also, BRG1 interacts with β-catenin to promote target-gene activation in colon cancer cells (Barker et al, 2001). In patients with intellectual disability, ARID1B represses BRG1 -dependent Wnt/β-catenin signaling (Vasileiou et al, 2015). …”

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

“…(fold regulation of ϽϪ2), except that the bacterial load in ARID1B siRNA-transfected cells increased. ARID1B is an AT-rich DNA-interacting domain-containing protein and a component of the SWI/SNF chromatinremodeling complex, and it has been reported to interact with ␤-catenin to suppress Wnt signaling (49). The results suggest that TRP120 plays a major role in influencing Wnt pathway activation by interacting with these Wnt pathway regulators during E. chaffeensis infection.…”

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

“…First, the two paralogs seem to associate with different sets of transcription factors (Raab et al, 2015). Second, genetic mouse models suggest that the two proteins are functionally distinct (Celen et al, 2017; Goldman et al, 2016; Krosl et al, 2010; Vasileiou et al, 2015; Zhai et al, 2016). As a matter of fact, we found a subset of 1,817 genes that are not entirely rescued by ARID1B expression and remain dysregulated.…”