Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCA1
Cytogenetic location: Xq25-q26.1 Genomic coordinates (GRCh38): X:129,446,506-129,523,490 (from NCBI)
In the course of positional cloning of genes carried on YACs that span the breakpoint in a t(X;3) translocation in a female with Lowe syndrome (309000), Okabe et al. (1992) isolated by chance a human gene with strong homology to SNF2 in S. cerevisiae. Despite strong homology at the amino acid level, the SNF2L1 gene in the human was not capable of complementing the yeast mutation. Furthermore, in contrast to SNF2 itself, a fusion protein consisting of the DNA binding domain of LexA and the human gene did not transactivate a reporter gene downstream of LexA binding sites in a yeast expression system. The similarity between SNF2L1 and the yeast gene suggested that the mammalian gene is part of an evolutionarily conserved family that has been implicated as a global activator of transcription in yeast, but its function in mammals remains unknown. See also SNF2L2 (600014) and ATRX (300032).
Lazzaro and Picketts (2001) cloned the murine homologs of the Drosophila 'imitation switch' (ISWI) protein, Snf2h (SMARCA5; 603375) and Snf2l. In situ hybridization of mouse adult tissues and embryos showed that Snf2h expression correlated with cell proliferation, while Snf2l expression correlated with differentiation. Snf2l was expressed in terminally differentiated neurons after birth and in adult mice, as well as in adult ovaries and testes.
By in situ hybridization and immunolabeling, Alvarez-Saavedra et al. (2014) showed that Snf2h was robustly expressed in hindbrain progenitors in mouse brain, and that Snf2h and Snf2l protein expression was dynamically modulated during postnatal cerebellar development.
Okabe et al. (1992) mapped the SMARCA1 gene to chromosome X.
Banting et al. (2005) generated a mutant mouse line containing a gene trap insertion within Cecr2 (607576). Cecr2 expression was predominantly neural in the embryo, and mice homozygous for the Cecr2 gene trap insertion showed a high penetrance of exencephaly, which is the human equivalent of anencephaly, in a strain-dependent fashion. In HEK293 cells, they isolated CECR2 and SMARCA1 as components of a complex, which they termed CECR2-containing remodeling factor (CERF). CERF was capable of remodeling chromatin in vitro and displayed an ATP-hydrolyzing activity that was stimulated by nucleosomes. Banting et al. (2005) suggested that CERF plays a critical role in neurulation.
Alvarez-Saavedra et al. (2014) found that mice with conditional knockout of Snf2h in neural progenitors by embryonic day-11 (E11) were born at normal mendelian ratios but had significantly reduced body weight, being approximately half the size of controls by postnatal day-20 (P20). Brains from mutant mice were reduced in size with cerebellar hypoplasia by P40. Mutant mice displayed severe motor defects with ataxia-like symptoms and died prematurely around P25 to P40. Mice with conditional double knockout of Snf2h and Snf2l around the same embryonic day did not survive past birth. The authors generated mice with conditional knockout of Snf2h or conditional double knockout of Snf2h and Snf2l in postmitotic Purkinje cells (PCs) after P10. Mice of both genotypes were born at normal mendelian ratios and survived into adulthood. Behavioural studies showed that loss of Snf2h in postmitotic PCs did not cause motor deficits but rather caused cognitive alterations. Snf2h loss affected granule neuron progenitor (GNP) and PC progenitor expansion due to a cell-intrinsic defect, likely leading to cerebellar hypoplasia in Snf2h conditional knockout mice. Microarray and RT-PCR analyses revealed that Snf2h and Snf2l comodulated expression of En1 (131290). When both Snf2h and Snf2l were present, the endogenous role of Snf2l was to repress En1 transcription. However, in the absence of Snf2h, Snf2l was upregulated to restore En1 expression and early PC functions temporarily.
Alvarez-Saavedra, M., De Repentigny, Y., Lagali, P. S., Raghu Ram, E. V., Yan, K., Hashem, E., Ivanochko, D., Huh, M. S., Yang, D., Mears, A. J., Todd, M. A., Corcoran, C. P., and 11 others. Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation. Nature Commun. 5: 4181, 2014. [PubMed: 24946904] [Full Text: https://doi.org/10.1038/ncomms5181]
Banting, G. S., Barak, O., Ames, T. M., Burnham, A. C., Kardel, M. D., Cooch, N. S., Davidson, C. E., Godbout, R., McDermid, H. E., Shiekhattar, R. CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L. Hum. Molec. Genet. 14: 513-524, 2005. [PubMed: 15640247] [Full Text: https://doi.org/10.1093/hmg/ddi048]
Lazzaro, M. A., Picketts, D. J. Cloning and characterization of the murine Imitation Switch (ISWI) genes: differential expression patterns suggest distinct developmental roles for Snf2h and Snf2l. J. Neurochem. 77: 1145-1156, 2001. [PubMed: 11359880] [Full Text: https://doi.org/10.1046/j.1471-4159.2001.00324.x]
Okabe, I., Bailey, L. C., Attree, O., Srinivasan, S., Perkel, J. M., Laurent, B. C., Carlson, M., Nelson, D. L., Nussbaum, R. L. Cloning of human and bovine homologs of SNF2/SWI2: a global activator of transcription in yeast S. cerevisiae. Nucleic Acids Res. 20: 4649-4655, 1992. [PubMed: 1408766] [Full Text: https://doi.org/10.1093/nar/20.17.4649]