The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ
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31 October 2018
Letter |
Abstract
Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at very high frequencies in a variety of human malignancies, suggesting a widespread role for the SWI/SNF complex in tumour suppression1. However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A–SWI/SNF) operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ2. Using a combination of gain- and loss-of-function approaches in several cellular contexts, we show that YAP/TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits and liver tumorigenesis. We found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A–SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A–SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signalling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A–SWI/SNF, thereby preventing the formation of the ARID1A–SWI/SNF–YAP/TAZ complex, in favour of an association between TEAD and YAP/TAZ. We propose that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signalling, and inhibition of ARID1A–SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. This study offers a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis.
/////////////Mammalian SWI/SNF--a subunit BAF250/ARID1 is an E3 ubiquitin ligase that targets histone H2B. Li XS et al. The mammalian SWI/SNF chromatin-remodeling complex facilitates DNA access by transcription factors and the transcription machinery. The characteristic member of human SWI/SNF-A is BAF250/ARID1, of which there are two isoforms, BAF250a/ARID1a and BAF250b/ARID1b. Here we report that BAF250b complexes purified from mammalian cells contain elongin C (Elo C), a BC box binding component of an E3 ubiquitin ligase. BAF250b was found to have a BC box motif, associate with Elo C in a BC box-dependent manner, and, together with cullin 2 and Roc1, assemble into an E3 ubiquitin ligase. The BAF250b BC box mutant protein was unstable in vivo and was autoubiquitinated in a manner similar to that for the VHL BC box mutants. The discovery that BAF250 is part of an E3 ubiquitin ligase adds an enzymatic function to the chromatin-remodeling complex SWI/SNF-A. The immunopurified BAF250b E3 ubiquitin ligase was found to target histone H2B at lysine 120 for monoubiquitination in vitro. To date, all H2B monoubiquitination was attributed to the human homolog of yeast Bre1 (RNF20/40). Mutation of Drosophila osa, the homolog of BAF250, or depletion of BAF250 by RNA interference (RNAi) in cultured human cells resulted in global decreases in monoubiquitinated H2B, implicating BAF250 in the cross talk of histone modifications.
NCBI Summary:
This gene encodes a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
General function
Nucleic acid binding
, Epigenetic modifications
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Cellular localization
Nuclear
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Ovarian function
Antral follicle growth, Early embryo development
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Expression of ARID1A in polycystic ovary syndrome and its effect on the proliferation and apoptosis of ovarian granulosa cells. Ji XL et al. (2020) The purpose of the present study was to clarify the expression of ARID1A in polycystic ovary syndrome (PCOS) and its effect on ovarian granulosa cells (GCs). Serum samples were collected from PCOS patients to detect the expression of ARID1A by qRT-PCR. Then, mouse and human ovarian GCs were isolated and divided into several groups according to difference in transfection, and the following experiments were performed: MTT assay, flow cytometry, qRT-PCR, radioimmunoassay, and Western blotting. ARID1A was down-regulated in the serum of PCOS patients and ovarian GCs from PCOS mice. Human and mouse ovarian GCs in the ARID1A group and LY294002 group showed decreased proliferation and increased apoptosis compared to those in the mock group, and showed a higher percentage of G0/G1 phase and lower percentage of S phase or G2/M. Moreover, the expression of steroid metabolism-related genes (3βHSD, Cyp11a1, StAR and Cyp19a1) in these two groups was down-regulated, with lower levels of estradiol (E2) and progesterone (P). In addition, protein expression of cleaved caspase-3 was increased while expression of p-Akt/Akt and cyclin D1 was decreased. However, the levels of the above indicators in the si-ARID1A group showed totally different changes. Furthermore, LY294002, the PI3K/Akt pathway inhibitor, could reverse the effect of si-ARID1A on the ovarian GCs. ARID1A was down-regulated in PCOS, while ARID1A overexpression can suppress the PI3K/Akt pathway to inhibit proliferation and promote apoptosis in ovarian granulosa cells.//////////////////
ARID1A, a component of SWI/SNF chromatin remodeling complexes, is required for porcine embryo development. Tseng YC et al. (2017) Mammalian embryos undergo dramatic epigenetic remodeling that can have a profound impact on both gene transcription and overall embryo developmental competence. Members of the SWI/SNF (Switch/Sucrose non-fermentable) family of chromatin-remodeling complexes reposition nucleosomes and alter transcription factor accessibility. These large, multi-protein complexes possess an SNF2-type ATPase (either SMARCA4 or SMARCA2) as their core catalytic subunit, and are directed to specific loci by associated subunits. Little is known about the identity of specific SWI/SNF complexes that serve regulatory roles during cleavage development. ARID1A, one of the SWI/SNF complex subunits, can affect histone methylation in somatic cells; here, we determined the developmental requirements of ARID1A in porcine oocytes and embryos. We found ARID1A transcript levels were significantly reduced in 4-cell porcine embryos as compared to germinal vesicle-stage oocytes, suggesting that ARID1A would be required for porcine cleavage-stage development. Indeed, injecting in vitro-matured and fertilized porcine oocytes with double-stranded interfering RNAs that target ARID1A, and evaluating their phenotype after seven days, revealed that the depletion of ARID1A results in significantly fewer cells than their respective control groups (p < 0.001).//////////////////
Expression regulated by
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Ovarian localization
Oocyte, Granulosa, Ovarian tumor
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Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma. Jones S et al. Ovarian clear cell carcinoma (OCCC) is an aggressive human cancer that is generally resistant to therapy. To explore the genetic origin of OCCC, we determined the exomic sequences of eight tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, we identified four genes that were mutated in at least two tumors. PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well known oncoprotein, had previously been implicated in OCCC. The other two mutated genes were novel: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2, and ARID1A encodes AT-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC.
Follicle stages
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Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: infertile - non-ovarian defect Comment: Deletion of Arid1a in Reproductive Tract Mesenchymal Cells Reduces Fertility in Female Mice. Wang X et al. (2016) Women with endometriosis can suffer from decreased fecundity or complete infertility via abnormal oocyte function or impaired placental-uterine interactions required for normal pregnancy establishment and maintenance. Although AT-rich interactive domain 1A (SWI-like) (ARID1A) is a putative tumor suppressor in human endometrial cancers and endometriosis-associated ovarian cancers, little is known about its role in normal uterine function. To study the potential function of ARID1A in the female reproductive tract, we generated mice with a conditional knockout of Arid1a using anti-Müllerian hormone receptor 2-Cre. Female Arid1a conditional knockout mice exhibited a progressive decrease in number of pups per litter, with a precipitous decline after the second litter. We observed no tumors in virgin mice, although one knockout mouse developed a uterine tumor after pregnancy. Unstimulated virgin female knockout mice showed normal oviductal, ovarian, and uterine histology. Uteri of Arid1a knockout mice showed a normal decidualization response and appropriate responses to estradiol and progesterone stimulation. In vitro studies using primary cultures of human endometrial stromal fibroblasts revealed that siRNA knockdown of ARID1A did not affect decidualization in vitro. Timed pregnancy studies revealed the significant resorption of embryos at Embryonic Day 16.5 in knockout mice in the third pregnancy. In addition to evidence of implantation site hemorrhage, pregnant Arid1a knockout mice showed abnormal placental morphology. These results suggest that Arid1a supports successful pregnancy through its role in placental function.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Deletion of BAF250a affects oocyte epigenetic modifications and embryonic development. Zhou Q et al. (2020) BRG1-associated factor 250a (BAF250a) is a component of the SWI/SNF adenosine triphosphate-dependent chromatin remodeling complex, which has been shown to control chromatin structure and transcription. BAF250a was reported to be a key component of the gene regulatory machinery in embryonic stem cells controlling self-renewal, differentiation, and cell lineage decisions. Here we constructed Baf250aF/F ;Gdf9-cre (Baf250aCKO ) mice to specifically delete BAF250a in oocytes to investigate the role of maternal BAF250a in female germ cells and embryo development. Our results showed that BAF250a deletion did not affect folliculogenesis, ovulation, and fertilization, but it caused late embryonic death. RNA sequencing analysis showed that the expression of genes involved in cell proliferation and differentiation, tissue morphogenesis, histone modification, and nucleosome remodeling were perturbed in Baf250aCKO MII oocytes. We showed that covalent histone modifications such as H3K27me3 and H3K27ac were also significantly affected in oocytes, which may reduce oocyte quality and lead to birth defects. In addition, the DNA methylation level of Igf2r, Snrpn, and Peg3 differentially methylated regions was decreased in Baf250aCKO oocytes. Quantitative real-time polymerase chain reaction analysis showed that the relative messenger RNA (mRNA) expression levels of Igf2r and Snrpn were significantly increased. The mRNA expression level of Dnmt1, Dnmt3a, Dnmt3l, and Uhrf1 was decreased, and the protein expression in these genes was also reduced, which might be the cause for impaired imprinting establishment. In conclusion, our results demonstrate that BAF250a plays an important role in oocyte transcription regulation, epigenetic modifications, and embryo development.//////////////////