SMARCA4

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

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
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 21,616,169 bp[2] End 21,704,230 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • nucleotide binding • GO:0001105 transcription coactivator activity • DNA-dependent ATPase activity • GO:0001187 RNA polymerase I core promoter sequence-specific DNA binding • GO:0008026 helicase activity • GO:0001106 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 • GO:0001948 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 • nuclear chromatin • cell nucleus • extracellular • macromolecular complex Biological process • positive regulation of glucose mediated signaling pathway • chromatin remodeling • regulation of transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • positive regulation of transcription of nuclear large rRNA transcript from RNA polymerase I promoter • negative regulation of androgen receptor signaling pathway • positive regulation of sequence-specific DNA binding transcription factor activity • negative regulation of transcription from RNA polymerase II promoter • transcription, DNA-templated • nervous system development • ATP-dependent chromatin remodeling • 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 from RNA polymerase II promoter • positive regulation by host of viral transcription • neural retina development • positive regulation of transcription from RNA polymerase II promoter • beta-catenin-TCF complex assembly • covalent chromatin modification • nucleosome disassembly • negative regulation of transcription, DNA-templated • chromatin organization • interleukin-7-mediated signaling pathway • RNA polymerase I transcriptional 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: 21.62 – 21.7 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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]

Clinical significance

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]

Interactions

SMARCA4 has been shown to interact with:

• ACTL6A,[20][21]
• ARID1A,[20][21]
• ARID1B,[22][23]
• BRCA1,[24][25]
• CTNNB1,[26]
• CBX5,[27]
• CREBBP,[28][29]
• CCNE1,[30][31]
• ESR1,[28][32]
• FANCA,[33][34]
• HSP90B1,[33]
• ING1,[35]
• Myc,[36][37]
• NR3C1,[38][39]
• P53,[40]
• POLR2A,[20][21][41]
• PHB,[42]
• SIN3A,[35][41]
• SMARCB1,[20][21][33][41][43]
• SMARCC1,[20][21][33][41]
• SMARCC2,[20][21][33]
• SMARCE1,[20][21]
• STAT2,[44] and
• STK11.[45]

References

1. GRCh38: Ensembl release 89: ENSG00000127616 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032187 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Chiba H, Muramatsu M, Nomoto A, Kato H (May 1994). "Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor". Nucleic Acids Research. 22 (10): 1815–20. doi:10.1093/nar/22.10.1815. PMC 308079. PMID 8208605.
6. "Entrez Gene: SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4".
7. Kim Y, Fedoriw AM, Magnuson T (March 2012). "An essential role for a mammalian SWI/SNF chromatin-remodeling complex during male meiosis". Development. 139 (6): 1133–40. doi:10.1242/dev.073478. PMC 3283123. PMID 22318225.
8. Zhang M, Chen M, Kim JR, Zhou J, Jones RE, Tune JD, Kassab GS, Metzger D, Ahlfeld S, Conway SJ, Herring BP (July 2011). "SWI/SNF complexes containing Brahma or Brahma-related gene 1 play distinct roles in smooth muscle development". Molecular and Cellular Biology. 31 (13): 2618–31. doi:10.1128/MCB.01338-10. PMC 3133369. PMID 21518954.
9. Hodges C, Kirkland JG, Crabtree GR (August 2016). "The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer". Cold Spring Harbor Perspectives in Medicine. 6 (8): a026930. doi:10.1101/cshperspect.a026930. PMC 4968166. PMID 27413115.
10. Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann M, Crabtree GR, Goff SP (October 1994). "The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest". Cell. 79 (1): 119–30. doi:10.1016/0092-8674(94)90405-7. PMID 7923370.
11. Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J, Sanchez-Cespedes M (May 2008). "Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines". Human Mutation. 29 (5): 617–22. doi:10.1002/humu.20730. PMID 18386774.
12. Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, et al. (August 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature. 488 (7409): 100–5. doi:10.1038/nature11284. PMC 3662966. PMID 22832583.
13. Shain AH, Giacomini CP, Matsukuma K, Karikari CA, Bashyam MD, Hidalgo M, Maitra A, Pollack JR (January 2012). "Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer". Proceedings of the National Academy of Sciences of the United States of America. 109 (5): E252–9. doi:10.1073/pnas.1114817109. PMC 3277150. PMID 22233809.
14. Shain AH, Pollack JR (2013). "The spectrum of SWI/SNF mutations, ubiquitous in human cancers". PLOS ONE. 8 (1): e55119. doi:10.1371/journal.pone.0055119. PMC 3552954. PMID 23355908.
15. Hodges HC, Stanton BZ, Cermakova K, Chang CY, Miller EL, Kirkland JG, Ku WL, Veverka V, Zhao K, Crabtree GR (January 2018). "Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers". Nature Structural & Molecular Biology. 25 (1): 61–72. doi:10.1038/s41594-017-0007-3. PMC 5909405. PMID 29323272.
16. Stanton BZ, Hodges C, Calarco JP, Braun SM, Ku WL, Kadoch C, Zhao K, Crabtree GR (February 2017). "Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin". Nature Genetics. 49 (2): 282–288. doi:10.1038/ng.3735. PMC 5373480. PMID 27941795.
17. Romero OA, Sanchez-Cespedes M (May 2014). "The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases". Oncogene. 33 (21): 2681–9. doi:10.1038/onc.2013.227. PMID 23752187.
18. Romero OA, Setien F, John S, Gimenez-Xavier P, Gómez-López G, Pisano D, Condom E, Villanueva A, Hager GL, Sanchez-Cespedes M (July 2012). "The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer". EMBO Molecular Medicine. 4 (7): 603–16. doi:10.1002/emmm.201200236. PMC 3407948. PMID 22407764.
19. Garnier N, Petruccelli LA, Molina MF, Kourelis M, Kwan S, Diaz Z, Schipper HM, Gupta A, del Rincon SV, Mann KK, Miller WH (November 2013). "The novel arsenical Darinaparsin circumvents BRG1-dependent, HO-1-mediated cytoprotection in leukemic cells". Leukemia. 27 (11): 2220–8. doi:10.1038/leu.2013.54. PMID 23426167.
20. Wang W, Côté J, Xue Y, Zhou S, Khavari PA, Biggar SR, Muchardt C, Kalpana GV, Goff SP, Yaniv M, Workman JL, Crabtree GR (October 1996). "Purification and biochemical heterogeneity of the mammalian SWI-SNF complex". The EMBO Journal. 15 (19): 5370–82. doi:10.1002/j.1460-2075.1996.tb00921.x. PMC 452280. PMID 8895581.
21. Zhao K, Wang W, Rando OJ, Xue Y, Swiderek K, Kuo A, Crabtree GR (November 1998). "Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling". Cell. 95 (5): 625–36. doi:10.1016/S0092-8674(00)81633-5. PMID 9845365.
22. Hurlstone AF, Olave IA, Barker N, van Noort M, Clevers H (May 2002). "Cloning and characterization of hELD/OSA1, a novel BRG1 interacting protein". The Biochemical Journal. 364 (Pt 1): 255–64. doi:10.1042/bj3640255. PMC 1222568. PMID 11988099.
23. Inoue H, Furukawa T, Giannakopoulos S, Zhou S, King DS, Tanese N (November 2002). "Largest subunits of the human SWI/SNF chromatin-remodeling complex promote transcriptional activation by steroid hormone receptors". The Journal of Biological Chemistry. 277 (44): 41674–85. doi:10.1074/jbc.M205961200. PMID 12200431.
24. Hill DA, de la Serna IL, Veal TM, Imbalzano AN (April 2004). "BRCA1 interacts with dominant negative SWI/SNF enzymes without affecting homologous recombination or radiation-induced gene activation of p21 or Mdm2". Journal of Cellular Biochemistry. 91 (5): 987–98. doi:10.1002/jcb.20003. PMID 15034933.
25. Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS, Wang W, Kashanchi F, Shiekhattar R (July 2000). "BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer". Cell. 102 (2): 257–65. doi:10.1016/S0092-8674(00)00030-1. PMID 10943845.
26. Barker N, Hurlstone A, Musisi H, Miles A, Bienz M, Clevers H (September 2001). "The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation". The EMBO Journal. 20 (17): 4935–43. doi:10.1093/emboj/20.17.4935. PMC 125268. PMID 11532957.
27. Nielsen AL, Sanchez C, Ichinose H, Cerviño M, Lerouge T, Chambon P, Losson R (November 2002). "Selective interaction between the chromatin-remodeling factor BRG1 and the heterochromatin-associated protein HP1alpha". The EMBO Journal. 21 (21): 5797–806. doi:10.1093/emboj/cdf560. PMC 131057. PMID 12411497.
28. DiRenzo J, Shang Y, Phelan M, Sif S, Myers M, Kingston R, Brown M (October 2000). "BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation". Molecular and Cellular Biology. 20 (20): 7541–9. doi:10.1128/MCB.20.20.7541-7549.2000. PMC 86306. PMID 11003650.
29. Neish AS, Anderson SF, Schlegel BP, Wei W, Parvin JD (February 1998). "Factors associated with the mammalian RNA polymerase II holoenzyme". Nucleic Acids Research. 26 (3): 847–53. doi:10.1093/nar/26.3.847. PMC 147327. PMID 9443979.
30. Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K, Ghaffari S, Iliev D, Penn B, Woodland AM, Smith R, Salada G, Carillo A, Laity K, Gupte J, Swedlund B, Tavtigian SV, Teng DH, Lees E (November 2000). "BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines". Cancer Research. 60 (21): 6171–7. PMID 11085541.
31. Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (February 1999). "Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest". Molecular and Cellular Biology. 19 (2): 1460–9. doi:10.1128/mcb.19.2.1460. PMC 116074. PMID 9891079.
32. Ichinose H, Garnier JM, Chambon P, Losson R (March 1997). "Ligand-dependent interaction between the estrogen receptor and the human homologues of SWI2/SNF2". Gene. 188 (1): 95–100. doi:10.1016/S0378-1119(96)00785-8. PMID 9099865.
33. Otsuki T, Furukawa Y, Ikeda K, Endo H, Yamashita T, Shinohara A, Iwamatsu A, Ozawa K, Liu JM (November 2001). "Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex". Human Molecular Genetics. 10 (23): 2651–60. doi:10.1093/hmg/10.23.2651. PMID 11726552.
34. Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H, Gross HJ, Joenje H, Hoatlin ME, Mathew CG, Huber PA (October 2003). "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Experimental Cell Research. 289 (2): 211–21. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622.
35. Kuzmichev A, Zhang Y, Erdjument-Bromage H, Tempst P, Reinberg D (February 2002). "Role of the Sin3-histone deacetylase complex in growth regulation by the candidate tumor suppressor p33(ING1)". Molecular and Cellular Biology. 22 (3): 835–48. doi:10.1128/MCB.22.3.835-848.2002. PMC 133546. PMID 11784859.
36. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
37. Park J, Wood MA, Cole MD (March 2002). "BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation". Molecular and Cellular Biology. 22 (5): 1307–16. doi:10.1128/MCB.22.5.1307-1316.2002. PMC 134713. PMID 11839798.
38. Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK (September 2003). "BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation". Molecular and Cellular Biology. 23 (17): 6210–20. doi:10.1128/MCB.23.17.6210-6220.2003. PMC 180928. PMID 12917342.
39. Wallberg AE, Neely KE, Hassan AH, Gustafsson JA, Workman JL, Wright AP (March 2000). "Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau1 activation domain". Molecular and Cellular Biology. 20 (6): 2004–13. doi:10.1128/MCB.20.6.2004-2013.2000. PMC 110817. PMID 10688647.
40. Lee D, Kim JW, Seo T, Hwang SG, Choi EJ, Choe J (June 2002). "SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription". The Journal of Biological Chemistry. 277 (25): 22330–7. doi:10.1074/jbc.M111987200. PMID 11950834.
41. Sif S, Saurin AJ, Imbalzano AN, Kingston RE (March 2001). "Purification and characterization of mSin3A-containing Brg1 and hBrm chromatin remodeling complexes". Genes & Development. 15 (5): 603–18. doi:10.1101/gad.872801. PMC 312641. PMID 11238380.
42. Wang S, Zhang B, Faller DV (June 2002). "Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth". The EMBO Journal. 21 (12): 3019–28. doi:10.1093/emboj/cdf302. PMC 126057. PMID 12065415.
43. Sullivan EK, Weirich CS, Guyon JR, Sif S, Kingston RE (September 2001). "Transcriptional activation domains of human heat shock factor 1 recruit human SWI/SNF". Molecular and Cellular Biology. 21 (17): 5826–37. doi:10.1128/MCB.21.17.5826-5837.2001. PMC 87302. PMID 11486022.
44. Huang M, Qian F, Hu Y, Ang C, Li Z, Wen Z (October 2002). "Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes". Nature Cell Biology. 4 (10): 774–81. doi:10.1038/ncb855. PMID 12244326.
45. Marignani PA, Kanai F, Carpenter CL (August 2001). "LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest". The Journal of Biological Chemistry. 276 (35): 32415–8. doi:10.1074/jbc.C100207200. PMID 11445556.

Further reading

• Medina PP, Sanchez-Cespedes M, Cespedes MS (2008). "Involvement of the chromatin-remodeling factor BRG1/SMARCA4 in human cancer". Epigenetics. 3 (2): 64–8. doi:10.4161/epi.3.2.6153. PMID 18437052.
• Voellmy R (1996). Sensing stress and responding to stress. Exs. 77. pp. 121–37. doi:10.1007/978-3-0348-9088-5_9. ISBN 978-3-0348-9901-7. PMID 8856972.
• Peterson CL (April 2002). "Chromatin remodeling: nucleosomes bulging at the seams". Current Biology. 12 (7): R245–7. doi:10.1016/S0960-9822(02)00782-0. PMID 11937040.

External links

• FactorBook Brg1