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2015 ; 97
(3
): 445-56
Nephropedia Template TP
Vasileiou G
; Ekici AB
; Uebe S
; Zweier C
; Hoyer J
; Engels H
; Behrens J
; Reis A
; Hadjihannas MV
Am J Hum Genet
2015[Sep]; 97
(3
): 445-56
PMID26340334
show ga
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.
|Blotting, Western
[MESH]
|Chromatin Assembly and Disassembly/*genetics
[MESH]
free
free
free
