SMARCA4

SMARCA4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2GRC, 2H60, 3UVD, 5DKD, 5EA1
Identifiers
Aliases	SMARCA4, BAF190, BAF190A, BRG1, MRD16, RTPS2, SNF2, SNF2L4, SNF2LB, SWI2, hSNF2b, CSS4, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
External IDs	OMIM: 603254; MGI: 88192; HomoloGene: 135927; GeneCards: SMARCA4; OMA:SMARCA4 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.2 Start 10,961,001 bp[1] End 11,065,395 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A3|9 7.84 cM Start 21,527,465 bp[2] End 21,615,526 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence tendon of biceps brachii ventricular zone amniotic fluid epithelium of nasopharynx sural nerve middle temporal gyrus primary visual cortex endothelial cell right hemisphere of cerebellum Top expressed in Rostral migratory stream otic vesicle hand ganglionic eminence mandibular prominence somite tail of embryo internal carotid artery Gonadal ridge maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function RNA polymerase II cis-regulatory region sequence-specific DNA binding nucleotide binding transcription coactivator activity ATP-dependent activity, acting on DNA RNA polymerase I core promoter sequence-specific DNA binding helicase activity transcription corepressor activity protein N-terminus binding histone binding p53 binding transcription factor binding Tat protein binding DNA polymerase binding hydrolase activity, acting on acid anhydrides ATPase activity protein binding androgen receptor binding lysine-acetylated histone binding nucleosomal DNA binding hydrolase activity ATP binding RNA binding DNA binding Cellular component nBAF complex membrane SWI/SNF complex nucleoplasm npBAF complex nucleolus nucleus extracellular space protein-containing complex Biological process positive regulation of glucose mediated signaling pathway chromatin remodeling regulation of transcription, DNA-templated regulation of transcription by RNA polymerase II positive regulation of transcription of nucleolar large rRNA by RNA polymerase I negative regulation of androgen receptor signaling pathway positive regulation of DNA-binding transcription factor activity negative regulation of transcription by RNA polymerase II transcription, DNA-templated nervous system development positive regulation of transcription, DNA-templated positive regulation of Wnt signaling pathway negative regulation of G1/S transition of mitotic cell cycle negative regulation of cell growth positive regulation of pri-miRNA transcription by RNA polymerase II positive regulation by host of viral transcription neural retina development positive regulation of transcription by RNA polymerase II beta-catenin-TCF complex assembly nucleosome disassembly negative regulation of transcription, DNA-templated chromatin organization interleukin-7-mediated signaling pathway RNA polymerase I preinitiation complex assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6597 20586 Ensembl ENSG00000127616 ENSMUSG00000032187 UniProt P51532 Q9HBD4 Q3TKT4 RefSeq (mRNA) NM_001128844 NM_001128845 NM_001128846 NM_001128847 NM_001128848 NM_001128849 NM_003072 NM_001174078 NM_001174079 NM_011417 NM_001357764 RefSeq (protein) NP_001122316 NP_001122317 NP_001122318 NP_001122319 NP_001122320 NP_001122321 NP_003063 NP_001361386 NP_001122321.1 NP_001167549 NP_001167550 NP_035547 NP_001344693 Location (UCSC) Chr 19: 10.96 – 11.07 Mb Chr 9: 21.53 – 21.62 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.^[5]

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 SWI/SNF, 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.^[6]

BRG1 works to activate or repress transcription. Having functional BRG1 is important for development past the pre-implantation stage. Without having a functional BRG1, exhibited with knockout research, the embryo will not hatch out of the zona pellucida, which will inhibit implantation from occurring on the endometrium (uterine wall). BRG1 is also crucial to the development of sperm. During the first stages of meiosis in spermatogenesis there are high levels of BRG1. When BRG1 is genetically damaged, meiosis is stopped in prophase 1, hindering the development of sperm and would result in infertility. More knockout research has concluded BRG1’s aid in the development of smooth muscle. In a BRG1 knockout, smooth muscle in the gastrointestinal tract lacks contractility, and intestines are incomplete in some cases. Another defect occurring in knocking out BRG1 in smooth muscle development is heart complications such as an open ductus arteriosus after birth.^[7][8]

BRG1 (or SMARCA4) is the most frequently mutated chromatin remodeling ATPase in cancer.^[9] Mutations in this gene were first recognized in human cancer cell lines derived from adrenal gland^[10] and lung.^[11] Later it was recognized that mutations exist in a significant frequency of medulloblastoma and pancreatic cancers, and in many other tumor subtypes.^[12][13][14]

In cancer, mutations in BRG1 show an unusually high preference for missense mutations that are frequently heterozygous and target the ATPase domain.^[15][9] Mutations are enriched at highly conserved ATPase sequences,^[16] which lie on important functional surfaces such as the ATP pocket or DNA-binding surface.^[15] These mutations act in a genetically dominant manner to alter chromatin regulatory function at enhancers^[15] and promoters.^[16]

Mutations of BRG1 are associated with context-dependent expression changes at MYC-genes, which indicates that the BRG1 and MYC proteins are functionally related.^[15][11][17] Another study demonstrated a causal role of BRG1 in the control of retinoic acid and glucocorticoid-induced cell differentiation in lung cancer and in other tumor types. This enables the cancer cell to sustain undifferentiated gene expression programs that affect the control of key cellular processes. Furthermore, it explains why lung cancer and other solid tumors are completely refractory to treatments based on these compounds that are effective therapies for some types of leukemia.^[18]

The role of BRG1 in sensitivity or resistance to anti-cancer drugs had been recently highlighted by the elucidation of the mechanisms of action of darinaparsin, an arsenic-based anti-cancer drugs. Darinaparsin has been shown to induce phosphorylation of BRG1, which leads to its exclusion from chromatin. When excluded from the chromatin, BRG1 can no longer act as a transcriptional co-regulator. This leads to the inability of cells to express HO-1, a cytoprotective enzyme.^[19]

SMARCA4 has been shown to interact with:

• FactorBook Brg1