Article

# The BRG1 Chromatin Remodeler Protects Against Ovarian Cysts, Uterine Tumors, and Mammary Tumors in a Lineage-Specific Manner

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Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
(Impact Factor: 3.23). 02/2012; 7(2):e31346. DOI: 10.1371/journal.pone.0031346
Source: PubMed

ABSTRACT

The BRG1 catalytic subunit of SWI/SNF-related complexes is required for mammalian development as exemplified by the early embryonic lethality of Brg1 null homozygous mice. BRG1 is also a tumor suppressor and, in mice, 10% of heterozygous (Brg1(null/+)) females develop mammary tumors. We now demonstrate that BRG1 mRNA and protein are expressed in both the luminal and basal cells of the mammary gland, raising the question of which lineage requires BRG1 to promote mammary homeostasis and prevent oncogenic transformation. To investigate this question, we utilized Wap-Cre to mutate both Brg1 floxed alleles in the luminal cells of the mammary epithelium of pregnant mice where WAP is exclusively expressed within the mammary gland. Interestingly, we found that Brg1(Wap-Cre) conditional homozygotes lactated normally and did not develop mammary tumors even when they were maintained on a Brm-deficient background. However, Brg1(Wap-Cre) mutants did develop ovarian cysts and uterine tumors. Analysis of these latter tissues showed that both, like the mammary gland, contain cells that normally express Brg1 and Wap. Thus, tumor formation in Brg1 mutant mice appears to be confined to particular cell types that require BRG1 and also express Wap. Our results now show that such cells exist both in the ovary and the uterus but not in either the luminal or the basal compartments of the mammary gland. Taken together, these findings indicate that SWI/SNF-related complexes are dispensable in the luminal cells of the mammary gland and therefore argue against the notion that SWI/SNF-related complexes are essential for cell survival. These findings also suggest that the tumor-suppressor activity of BRG1 is restricted to the basal cells of the mammary gland and demonstrate that this function extends to other female reproductive organs, consistent with recent observations of recurrent ARID1A/BAF250a mutations in human ovarian and endometrial tumors.

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• ##### Article: Combined gene dosage requirement for SWI/SNF catalytic subunits during mammalian development
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ABSTRACT: Mammalian SWI/SNF complexes utilize either BRG1 or BRM as alternative catalytic subunits with DNA-dependent ATPase activity to remodel chromatin. Although the two proteins are 75 % identical, broadly expressed, and have similar biochemical activities in vitro, BRG1 is essential for mouse embryonic development, while BRM is dispensable. To investigate whether BRG1 and BRM have overlapping functions during mouse embryogenesis, we performed double-heterozygous intercrosses using constitutive null mutations previously created by gene targeting. The progeny of these crosses had a distribution of genotypes that was significantly skewed relative to their combined gene dosage. This was most pronounced at the top and bottom of the gene dosage hierarchy, with a 1.5-fold overrepresentation of Brg1 (+/+) ;Brm (+/+) mice and a corresponding 1.6-fold underrepresentation of Brg1 (+/-) ;Brm (-/-) mice. To account for the underrepresentation of Brg1 (+/-) ;Brm (-/-) mice, timed matings and blastocyst outgrowth assays demonstrated that ~50 % of these embryos failed to develop beyond the peri-implantation stage. These results challenge the idea that BRG1 is the exclusive catalytic subunit of SWI/SNF complexes in ES cells and suggest that BRM also interacts with the pluripotency transcription factors to facilitate self-renewal of the inner cell mass. In contrast to implantation, the Brm genotype did not influence an exencephaly phenotype that arises because of Brg1 haploinsufficiency during neural tube closure and that results in peri-natal lethality. Taken together, these results support the idea that BRG1 and BRM have overlapping functions for certain developmental processes but not others during embryogenesis.
Mammalian Genome 10/2012; 24(1). DOI:10.1007/s00335-012-9433-z · 3.07 Impact Factor
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##### Article: Nuclear Shape Changes Are Induced by Knockdown of the SWI/SNF ATPase BRG1 and Are Independent of Cytoskeletal Connections
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ABSTRACT: Changes in nuclear morphology occur during normal development and have been observed during the progression of several diseases. The shape of a nucleus is governed by the balance of forces exerted by nuclear-cytoskeletal contacts and internal forces created by the structure of the chromatin and nuclear envelope. However, factors that regulate the balance of these forces and determine nuclear shape are poorly understood. The SWI/SNF chromatin remodeling enzyme ATPase, BRG1, has been shown to contribute to the regulation of overall cell size and shape. Here we document that immortalized mammary epithelial cells show BRG1-dependent nuclear shape changes. Specifically, knockdown of BRG1 induced grooves in the nuclear periphery that could be documented by cytological and ultrastructural methods. To test the hypothesis that the observed changes in nuclear morphology resulted from altered tension exerted by the cytoskeleton, we disrupted the major cytoskeletal networks and quantified the frequency of BRG1-dependent changes in nuclear morphology. The results demonstrated that disruption of cytoskeletal networks did not change the frequency of BRG1-induced nuclear shape changes. These findings suggest that BRG1 mediates control of nuclear shape by internal nuclear mechanisms that likely control chromatin dynamics.
PLoS ONE 02/2013; 8(2):e55628. DOI:10.1371/journal.pone.0055628 · 3.23 Impact Factor
• ##### Article: Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids
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ABSTRACT: Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared to myometrium, it is likely most of these differences are a consequence of the fibroid presence, and are not causal. The aim of this study was to investigate expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used RT-qPCR, Western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid and sonic hedgehog conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared to matched myometrium, with strong blood vessel-specific localisation. Although the sonic hedgehog pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and retinoic acid combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures. In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared to normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development.
Reproduction 05/2013; 146(2). DOI:10.1530/REP-13-0087 · 3.17 Impact Factor
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