SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4)

2008-04-01   Pedro P Medina , Montse Sanchez-Cespedes 

Identity

HGNC
LOCATION
19p13.2
LOCUSID
ALIAS
BAF190,BAF190A,BRG1,CSS4,MRD16,RTPS2,SNF2,SNF2-beta,SNF2L4,SNF2LB,SWI2,hSNF2b
FUSION GENES

DNA/RNA

Atlas Image
Relative size of the 33 coding exons of SMARCA4. The entire exon 1 is UTR (untranslated region). Exon numeration corresponds to the prevalent transcript (matching the EST EU430759).

Description

The SMARCA4 is also known as BRG1 (hSWI/SNF brahma-related gene). It spans a total genomic size of 101347 bp and it is composed of 33 coding exons of varying lengths and 1 non-coding exon (exon 1).

Transcription

The human SMARCA4 transcript has approximately 5500 bp and contains an open reading frame of 4845 bp, predicting a protein of 1614 amino acid residues. There are different transcripts arising from two alternative splicing sites within intron 28 and exon 30, which predict the translation of four different BRG1 protein isoforms. In addition, between exon 26 and 27 and exon 29 and 30 there are two additional exons that may constitute tissue specific transcripts.

Proteins

Atlas Image
SMARCA4 conserved domains. Proline rich region, containing more than 25% of proline residues in the aminoacid sequence. HSA and BRK domains, containing motifs that may predict binding to DNA. ATPase/helicase domain, contains motifs present in the DEAD helicases superfamily, a diverse family of proteins involved in ATP-dependent RNA or DNA unwinding. Bromodomain, 110 aminoacid domain, found in many chromatin associated proteins. Bromodomains can interact specifically with acetylated lysine.

Description

SMARCA4 has a molecular mass of 181349 Da. SMARCA4 is the catalytic subunit of the chromatin-remodelling complex SWI-SNF and influences transcriptional regulation by disrupting histone-DNA contacts in an ATP-dependent manner. In addition to an ATPase, the SWI/SNF complex is composed of a variety of accessory proteins, termed BAFs (BRG-1-associated factors).

Expression

Widely expressed.

Localisation

SMARCA4 localizes in the nucleus.

Function

The SMARCA4 harbours the ATPase activity required for the chromatin remodelling activity of the SWI/SNF complex. This complex uses the energy of ATP hydrolysis to modify the interactions among histones leading to modifications of the chromatin structure and to the regulation of gene expression. The SWI/SNF complex plays a role in differentiation, development and cell cycle control. SMARCA4 binds to or it is related to important tumor suppressor proteins, including BRCA2, LKB1, RB and FANCA. Moreover, the SWI/SNF complex has been shown to modulate the transcriptional activity of steroid receptors (e.g. glucocorticoids receptors, retinoic acid receptors, androgen and estrogen receptors), CMYC and RB. SMARCA4 acts as a tumor suppressor because:
  • i) it induces cell-growth arrest after ectopic expression in deficient tumor cells;
  • ii) SMARCA4-heterozygous mice have an increased predisposition to tumor development and
  • iii) it is biallelically inactivated by homozygous deletions or combinations of deletions and mutations in several types of tumors, specially in lung cancer.
  • Homology

    The mammalian SWI/SNF complex contains either SMARCA4 or SMARCA2 as its central ATPase subunit. Both ATPases share 80% homology in their aminoacid sequence. However, differences in expression patterns and in the phenotypes of Brm and Brg1 knockout mice suggest specific biological roles between both ATPases.
    SMARCA2 and SMARCA4 are orthologous to the snf2/swi2 gene from S. cerevisiae and to the "brahma" (brm) gene from Drosophila. These encode proteins that are highly conserved along evolution, especially in the ATPase/helicase domain. Actually, SMARCA2 is 56% identical and 72% homologous to the Drosophila brm.

    Implicated in

    Entity name
    Various cancers
    Note
    SMARCA4 somatic mutations have been identified in some cancer cell lines including those from the lung, prostate, breast, pancreas and colon. While somatic mutations have been detected in a small subset of lung primary tumors, about one third of the lung cancer cell lines of the non-small cell lung cancer type harbour inactivating SMARCA4 somatic mutations. All mutations are homozygous and most of them predict truncated proteins. The type of mutations commonly observed include nonsense, indels and large deletions. Although less frequently, missense mutations have also been reported. Four of the aminoacid substitutions found in human lung and colorectal cancer, the p.W764R, p.G1160R, p.L1163P and p.S1176C represent changes in highly conserved residues within the ATPase/helicase domain. In vitro generated mutations of some highly conserved aminoacid within this motif lead to a seriously diminished catalytic activity of SMARCA4.
    SMARCA4 germ-line mutations have not been reported so far.
    Prognosis
    The lost of either SMARCA4 or SMARCA2, detected by immunostaining, predicts decreased survival in some cancer patients.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    111632032000A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes.Bultman S et al
    162877142005A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development.Bultman SJ et al
    106025151999Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary rhabdomyosarcomas but not Wilms' tumors.DeCristofaro MF et al
    111478082001Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies.Decristofaro MF et al
    152405172004Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer.Fukuoka J et al
    82325561993BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription.Khavari PA et al
    157311172005Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells.Medina PP et al
    183867742008Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines.Medina PP et al
    114207222001When the SWI/SNF complex remodels...the cell cycle.Muchardt C et al
    149643092004The SWI/SNF complex--chromatin and cancer.Roberts CW et al
    159880052005A conserved Swi2/Snf2 ATPase motif couples ATP hydrolysis to chromatin remodeling.Smith CL et al
    108844062000BRG-1 is required for RB-mediated cell cycle arrest.Strobeck MW et al
    96713071998Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer.Versteege I et al
    110855412000BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines.Wong AK et al

    Other Information

    Locus ID:

    NCBI: 6597
    MIM: 603254
    HGNC: 11100
    Ensembl: ENSG00000127616

    Variants:

    dbSNP: 6597
    ClinVar: 6597
    TCGA: ENSG00000127616
    COSMIC: SMARCA4

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000127616ENST00000344626P51532
    ENSG00000127616ENST00000344626A7E2E1
    ENSG00000127616ENST00000413806A0A0A0MT49
    ENSG00000127616ENST00000429416P51532
    ENSG00000127616ENST00000429416A7E2E1
    ENSG00000127616ENST00000444061P51532
    ENSG00000127616ENST00000450717Q9HBD4
    ENSG00000127616ENST00000538456A0A2R8YFK5
    ENSG00000127616ENST00000541122P51532
    ENSG00000127616ENST00000586985K7EQF0
    ENSG00000127616ENST00000589677P51532
    ENSG00000127616ENST00000590574P51532
    ENSG00000127616ENST00000591545A0A2R8YGP5
    ENSG00000127616ENST00000592158K7EP28
    ENSG00000127616ENST00000642350A0A2R8Y6N0
    ENSG00000127616ENST00000642508A0A2R8Y523
    ENSG00000127616ENST00000642628A0A2R8Y7S2
    ENSG00000127616ENST00000642726A0A2R8Y7S2
    ENSG00000127616ENST00000643208A0A2R8Y7F3
    ENSG00000127616ENST00000643296P51532
    ENSG00000127616ENST00000643534A0A2R8Y6V2
    ENSG00000127616ENST00000643549A0A2R8Y4P4
    ENSG00000127616ENST00000643857A0A2R8Y526
    ENSG00000127616ENST00000643995A0A2R8YGG3
    ENSG00000127616ENST00000644065A0A2R8Y440
    ENSG00000127616ENST00000644290A0A2R8Y7R0
    ENSG00000127616ENST00000644327A0A2R8Y4C5
    ENSG00000127616ENST00000644737P51532
    ENSG00000127616ENST00000644760A0A2R8Y866
    ENSG00000127616ENST00000644963A0A2R8YG32
    ENSG00000127616ENST00000645061A0A2R8YDA1
    ENSG00000127616ENST00000645236A0A2R8Y5K3
    ENSG00000127616ENST00000645387A0A2R8YF38
    ENSG00000127616ENST00000645460P51532
    ENSG00000127616ENST00000645648A0A2R8YCY3
    ENSG00000127616ENST00000646183A0A2R8YF80
    ENSG00000127616ENST00000646236A0A2R8Y4R6
    ENSG00000127616ENST00000646484P51532
    ENSG00000127616ENST00000646510P51532
    ENSG00000127616ENST00000646513A0A2R8YFV8
    ENSG00000127616ENST00000646593A0A2R8Y583
    ENSG00000127616ENST00000646693Q9HBD4
    ENSG00000127616ENST00000646746A0A2R8Y7Y7
    ENSG00000127616ENST00000647230P51532
    ENSG00000127616ENST00000647268A0A2R8YF58

    Expression (GTEx)

    0
    10
    20
    30
    40
    50
    60
    70
    80
    90

    Pathways

    PathwaySourceExternal ID
    Immune SystemREACTOMER-HSA-168256
    Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
    Signaling by InterleukinsREACTOMER-HSA-449147
    Interleukin-7 signalingREACTOMER-HSA-1266695
    Signal TransductionREACTOMER-HSA-162582
    Signaling by WntREACTOMER-HSA-195721
    TCF dependent signaling in response to WNTREACTOMER-HSA-201681
    Formation of the beta-catenin:TCF transactivating complexREACTOMER-HSA-201722
    Chromatin organizationREACTOMER-HSA-4839726
    Chromatin modifying enzymesREACTOMER-HSA-3247509
    RMTs methylate histone argininesREACTOMER-HSA-3214858

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    205960142010Chromatin regulation by Brg1 underlies heart muscle development and disease.182
    204189092010ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1.158
    126202262003Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes.139
    219004012011ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers.139
    125662962003Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis.111
    183867742008Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines.106
    183867742008Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines.106
    183867742008Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines.106
    246580022014Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.96
    236983692013BAF complexes facilitate decatenation of DNA by topoisomerase IIα.93

    Citation

    Pedro P Medina ; Montse Sanchez-Cespedes

    SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4)

    Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

    Online version: http://atlasgeneticsoncology.org/gene/42333/smarca4