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SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 OKDB#: 3325
 Symbols: SMARCA4 Species: human
 Synonyms: BRG1, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A  Locus: 19p13.2 in Homo sapiens


For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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General Comment A maternal effect gene

NCBI Summary: The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family 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. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
General function Nucleic acid binding, DNA binding, Transcription factor
Comment SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Le Loarer F et al. (2015) While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.//////////////////
Cellular localization Nuclear
Comment
Ovarian function Early embryo development, tumorigenesis
Comment Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Jelinic P 2014 et al. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, highly aggressive form of ovarian cancer primarily diagnosed in young women. We identified inactivating biallelic SMARCA4 mutations in 100% of the 12 SCCOHT tumors examined. Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT. /////////////////////////
Expression regulated by
Comment
Ovarian localization Oocyte, Granulosa, Theca, Ovarian tumor
Comment Pre- and Postovulatory Aging of Murine Oocytes Affect the Transcript Level and Poly(A) Tail Length of Maternal Effect Genes. Dankert D 2014 et al. Maternal effect genes code for oocyte proteins that are important for early embryogenesis. Transcription in oocytes does not take place from the onset of meiotic progression until zygotic genome activation. During this period, protein levels are regulated posttranscriptionally, for example by poly(A) tail length. Posttranscriptional regulation may be impaired in preovulatory and postovulatory aged oocytes, caused by delayed ovulation or delayed fertilization, respectively, and may lead to developmental defects. We investigated transcript levels and poly(A) tail length of ten maternal effect genes in in vivo- and in vitro- (follicle culture) grown oocytes after pre- and postovulatory aging. Quantitative RT-PCR was performed using random hexamer-primed cDNA to determine total transcript levels and oligo(dT)16-primed cDNA to analyze poly(A) tail length. Transcript levels of in vivo preovulatory-aged oocytes remained stable except for decreases in Brg1 and Tet3. Most genes investigated showed a tendency towards increased poly(A) content. Polyadenylation of in vitro preovulatory-aged oocytes was also increased, along with transcript level declines of Trim28, Nlrp2, Nlrp14 and Zar1. In contrast to preovulatory aging, postovulatory aging of in vivo- and in vitro-grown oocytes led to a shortening of poly(A) tails. Postovulatory aging of in vivo-grown oocytes resulted in deadenylation of Nlrp5 after 12 h, and deadenylation of 4 further genes (Tet3, Trim28, Dnmt1, Oct4) after 24 h. Similarly, transcripts of in vitro-grown oocytes were deadenylated after 12 h of postovulatory aging (Tet3, Trim28, Zfp57, Dnmt1, Nlrp5, Zar1). This impact of aging on poly(A) tail length may affect the timed translation of maternal effect gene transcripts and thereby contribute to developmental defects. ///////////////////////// Immunolocalization of BRG1-SWI/SNF protein during folliculogenesis in the porcine ovary. Lisboa LA et al. SummaryDynamic changes in chromatin structure and gene expression occur during follicular and oocyte growth. Epigenetic mechanisms regulate these changes through biochemical reactions that modify the nucleosome structure, and consequently affect transcription. Chromatin remodellers that alter DNA-histone interactions can influence transcriptional activity by facilitating or repressing DNA access. The SWItch/Sucrose NonFermentable (SWI/SNF) complex represents an important chromatin remodelling family, which comprises many protein subunits including the BRG1 (brahma-related gene 1). Our aim in this study was to analyse BRG1 expression patterns in different stages of follicular development. Ovaries (n = 10) were collected from prepubertal gilts and then rinsed in phosphate-buffered saline (PBS). Ovarian fragments of 8 ?8 ?8 mm were cut and placed into a 4% paraformaldehyde solution. For immunofluorescence analysis, samples were incubated with primary antibodies: polyclonal rabbit anti-BRG1 (1/200) or control rabbit IgG at the same concentration, overnight at 4?C. Primary antibodies were detected using Alexa Fluor 594-anti-rabbit 1/1000 diluted secondary antibody. Cells were counterstained with 4',6-diamidino-2-phenylindole (DAPI). Positive fluorescence signal for BRG1 was detected in all analysed samples. In primary follicles, the protein was detected only in the oocyte nucleus. However, in growing follicles, BRG1 was identified in granulosa and theca cells in a well defined pattern, according to the proximity of the cells from the oocyte. These results suggest an important role for BRG1 in the regulation of follicular growth, probably modulating granulosa and theca cell proliferation, as well as oocyte growth and maturation.
Follicle stages
Comment
Phenotypes
Mutations 2 mutations

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Maternal BRG1 regulates zygotic genome activation in the mouse. Bultman SJ et al. Zygotic genome activation (ZGA) is a nuclear reprogramming event that transforms the genome from transcriptional quiescence at fertilization to robust transcriptional activity shortly thereafter. The ensuing gene expression profile in the cleavage-stage embryo establishes totipotency and is required for further development. Although little is known about the molecular basis of ZGA, oocyte-derived mRNAs and proteins that alter chromatin structure are likely crucial. To test this hypothesis, we generated a maternal-effect mutation of Brg1, which encodes a catalytic subunit of SWI/SNF-related complexes, utilizing Cre-loxP gene targeting. In conditional-mutant females, BRG1-depleted oocytes completed meiosis and were fertilized. However, embryos conceived from BRG1-depleted eggs exhibited a ZGA phenotype including two-cell arrest and reduced transcription for approximately 30% of expressed genes. Genes involved in transcription, RNA processing, and cell cycle regulation were particularly affected. The early embryonic arrest is not a consequence of a defective oocyte because depleting maternal BRG1 after oocyte development is complete by RNA interference (RNAi) also resulted in two-cell arrest. To our knowledge, Brg1 is the first gene required for ZGA in mammals. Depletion of maternal BRG1 did not affect global levels of histone acetylation, whereas dimethyl-H3K4 levels were reduced. These data provide a framework for understanding the mechanism of ZGA.

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Witkowski L 2014 et al. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches. /////////////////////////

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created: July 5, 2006, 4:50 p.m. by: hsueh   email:
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last update: Sept. 9, 2015, 11:28 a.m. by: hsueh    email:



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