6lth

Structural highlights

Disease

[SMCE1_HUMAN] Familial multiple meningioma;Coffin-Siris syndrome. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [SMRC2_HUMAN] Coffin-Siris syndrome. The disease may be caused by mutations affecting the gene represented in this entry. [SMCA4_HUMAN] Defects in SMARCA4 are the cause of rhabdoid tumor predisposition syndrome type 2 (RTPS2) [MIM:613325]. RTPS2 is a familial cancer syndrome predisposing to renal or extrarenal malignant rhabdoid tumors and to a variety of tumors of the central nervous system, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumors. Rhabdoid tumors are the most aggressive and lethal malignancies occurring in early childhood.^[1] Defects in SMARCA4 are the cause of mental retardation autosomal dominant type 16 (MRD16) [MIM:614609]. A disease characterized by multiple congenital anomalies and mental retardation. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. MRD16 patients manifest developmental delay, absent or hypoplastic fifth fingernails or toenails, thick eyebrows and long eyelashes, hirsutism. Additional findings include hypotonia, microcephaly, seizures, a Dandy-Walker malformation, and vision and hearing problems.^[2] [SNF5_HUMAN] Neurofibromatosis type 3;Atypical teratoid rhabdoid tumor;Familial rhabdoid tumor;Familial multiple meningioma;Coffin-Siris syndrome. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [ARI1A_HUMAN] Defects in ARID1A are the cause of mental retardation autosomal dominant type 14 (MRD14) [MIM:614607]. A disease characterized by multiple congenital anomalies and mental retardation. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. MRD14 patients manifest developmental delay, abnormal corpus callosum, absent/hypoplastic fifth finger/toenails, sparse scalp hair, long eyelashes, and a coarse facial appearance with wide mouth, thick lips, and abnormal ears.^[3]

Function

[SMCE1_HUMAN] Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Required for the coactivation of estrogen responsive promoters by SWI/SNF complexes and the SRC/p160 family of histone acetyltransferases (HATs). Also specifically interacts with the CoREST corepressor resulting in repression of neuronal specific gene promoters in non-neuronal cells.[UniProtKB:O54941]^{[4] [5] [6]} [SMRC2_HUMAN] Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:11018012). Can stimulate the ATPase activity of the catalytic subunit of these complexes (PubMed:10078207). May be required for CoREST dependent repression of neuronal specific gene promoters in non-neuronal cells (PubMed:12192000). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation (By similarity).[UniProtKB:Q6PDG5]^{[7] [8] [9] [10] [11]} [SMCA4_HUMAN] Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating a calcium-dependent release of a repressor complex and a recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CREBBP. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues (By similarity). Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial-mesenchymal transition (EMT) by ZEB1.^{[12] [13] [14]} [SNF5_HUMAN] Core component of the BAF (hSWI/SNF) complex. This ATP-dependent chromatin-remodeling complex plays important roles in cell proliferation and differentiation, in cellular antiviral activities and inhibition of tumor formation. The BAF complex is able to create a stable, altered form of chromatin that constrains fewer negative supercoils than normal. This change in supercoiling would be due to the conversion of up to one-half of the nucleosomes on polynucleosomal arrays into asymmetric structures, termed altosomes, each composed of 2 histones octamers. Stimulates in vitro the remodeling activity of SMARCA4/BRG1/BAF190A. Involved in activation of CSF1 promoter. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Plays a key role in cell-cycle control and causes cell cycle arrest in G0/G1.^{[15] [16] [17] [18] [19] [20]} [REQU_HUMAN] May be a transcription factor required for the apoptosis response following survival factor withdrawal from myeloid cells. Might also have a role in the development and maturation of lymphoid cells. [ARI1A_HUMAN] Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Binds DNA non-specifically. Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).^[21] [SMRD1_HUMAN] Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:8804307, PubMed:29374058). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Has a strong influence on vitamin D-mediated transcriptional activity from an enhancer vitamin D receptor element (VDRE). May be a link between mammalian SWI-SNF-like chromatin remodeling complexes and the vitamin D receptor (VDR) heterodimer (PubMed:14698202). Mediates critical interactions between nuclear receptors and the BRG1/SMARCA4 chromatin-remodeling complex for transactivation (PubMed:12917342).[UniProtKB:Q61466]^{[22] [23] [24] [25] [26] [27]}

References

1. ↑ Schneppenheim R, Fruhwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, Kreuz M, Leuschner I, Martin Subero JI, Obser T, Oyen F, Vater I, Siebert R. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 2010 Feb 12;86(2):279-84. Epub 2010 Feb 4. PMID:20137775 doi:S0002-9297(10)00016-9
2. ↑ Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012 Mar 18;44(4):376-8. doi: 10.1038/ng.2219. PMID:22426308 doi:10.1038/ng.2219
3. ↑ Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012 Mar 18;44(4):376-8. doi: 10.1038/ng.2219. PMID:22426308 doi:10.1038/ng.2219
4. ↑ Martens JA, Winston F. Recent advances in understanding chromatin remodeling by Swi/Snf complexes. Curr Opin Genet Dev. 2003 Apr;13(2):136-42. PMID:12672490
5. ↑ Euskirchen G, Auerbach RK, Snyder M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J Biol Chem. 2012 Sep 7;287(37):30897-905. doi: 10.1074/jbc.R111.309302. Epub, 2012 Sep 5. PMID:22952240 doi:http://dx.doi.org/10.1074/jbc.R111.309302
6. ↑ Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015 Jun 12;1(5):e1500447. doi: 10.1126/sciadv.1500447. eCollection 2015, Jun. PMID:26601204 doi:http://dx.doi.org/10.1126/sciadv.1500447
7. ↑ Phelan ML, Sif S, Narlikar GJ, Kingston RE. Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol Cell. 1999 Feb;3(2):247-53. PMID:10078207
8. ↑ Kadam S, McAlpine GS, Phelan ML, Kingston RE, Jones KA, Emerson BM. Functional selectivity of recombinant mammalian SWI/SNF subunits. Genes Dev. 2000 Oct 1;14(19):2441-51. PMID:11018012
9. ↑ Battaglioli E, Andres ME, Rose DW, Chenoweth JG, Rosenfeld MG, Anderson ME, Mandel G. REST repression of neuronal genes requires components of the hSWI.SNF complex. J Biol Chem. 2002 Oct 25;277(43):41038-45. doi: 10.1074/jbc.M205691200. Epub 2002, Aug 20. PMID:12192000 doi:http://dx.doi.org/10.1074/jbc.M205691200
10. ↑ Euskirchen G, Auerbach RK, Snyder M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J Biol Chem. 2012 Sep 7;287(37):30897-905. doi: 10.1074/jbc.R111.309302. Epub, 2012 Sep 5. PMID:22952240 doi:http://dx.doi.org/10.1074/jbc.R111.309302
11. ↑ Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015 Jun 12;1(5):e1500447. doi: 10.1126/sciadv.1500447. eCollection 2015, Jun. PMID:26601204 doi:http://dx.doi.org/10.1126/sciadv.1500447
12. ↑ Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell. 2003 Jun 27;113(7):905-17. PMID:12837248
13. ↑ Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009 Jul 2;460(7251):66-72. doi: 10.1038/nature08137. PMID:19571879 doi:10.1038/nature08137
14. ↑ Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P, Postigo A. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010 Jun 17;29(24):3490-500. doi: 10.1038/onc.2010.102. Epub 2010 Apr, 26. PMID:20418909 doi:10.1038/onc.2010.102
15. ↑ Phelan ML, Sif S, Narlikar GJ, Kingston RE. Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol Cell. 1999 Feb;3(2):247-53. PMID:10078207
16. ↑ Versteege I, Medjkane S, Rouillard D, Delattre O. A key role of the hSNF5/INI1 tumour suppressor in the control of the G1-S transition of the cell cycle. Oncogene. 2002 Sep 19;21(42):6403-12. PMID:12226744 doi:http://dx.doi.org/10.1038/sj.onc.1205841
17. ↑ Oruetxebarria I, Venturini F, Kekarainen T, Houweling A, Zuijderduijn LM, Mohd-Sarip A, Vries RG, Hoeben RC, Verrijzer CP. P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells. J Biol Chem. 2004 Jan 30;279(5):3807-16. Epub 2003 Nov 6. PMID:14604992 doi:http://dx.doi.org/10.1074/jbc.M309333200
18. ↑ Pan X, Song Z, Zhai L, Li X, Zeng X. Chromatin-remodeling factor INI1/hSNF5/BAF47 is involved in activation of the colony stimulating factor 1 promoter. Mol Cells. 2005 Oct 31;20(2):183-8. PMID:16267391
19. ↑ Ulyanova NP, Schnitzler GR. Human SWI/SNF generates abundant, structurally altered dinucleosomes on polynucleosomal templates. Mol Cell Biol. 2005 Dec;25(24):11156-70. PMID:16314535 doi:http://dx.doi.org/10.1128/MCB.25.24.11156-11170.2005
20. ↑ Morozov A, Yung E, Kalpana GV. Structure-function analysis of integrase interactor 1/hSNF5L1 reveals differential properties of two repeat motifs present in the highly conserved region. Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1120-5. PMID:9448295
21. ↑ Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell. 2003 Jun 27;113(7):905-17. PMID:12837248
22. ↑ Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK. BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation. Mol Cell Biol. 2003 Sep;23(17):6210-20. PMID:12917342
23. ↑ Koszewski NJ, Henry KW, Lubert EJ, Gravatte H, Noonan DJ. Use of a modified yeast one-hybrid screen to identify BAF60a interactions with the Vitamin D receptor heterodimer. J Steroid Biochem Mol Biol. 2003 Dec;87(4-5):223-31. PMID:14698202
24. ↑ Alpsoy A, Dykhuizen EC. Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes. J Biol Chem. 2018 Mar 16;293(11):3892-3903. doi: 10.1074/jbc.RA117.001065. Epub, 2018 Jan 26. PMID:29374058 doi:http://dx.doi.org/10.1074/jbc.RA117.001065
25. ↑ Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 1996 Sep 1;10(17):2117-30. PMID:8804307
26. ↑ Euskirchen G, Auerbach RK, Snyder M. SWI/SNF chromatin-remodeling factors: multiscale analyses and diverse functions. J Biol Chem. 2012 Sep 7;287(37):30897-905. doi: 10.1074/jbc.R111.309302. Epub, 2012 Sep 5. PMID:22952240 doi:http://dx.doi.org/10.1074/jbc.R111.309302
27. ↑ Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015 Jun 12;1(5):e1500447. doi: 10.1126/sciadv.1500447. eCollection 2015, Jun. PMID:26601204 doi:http://dx.doi.org/10.1126/sciadv.1500447