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Shuying He, Jian Sun, Juraj Kokavec, Tomas Stopka, Arthur Skoultchi Skoultchi, Jiri Zavadil Zavadil, Ales Cvekl; Chromatin Remodeling Enzymes Snf2h/smarca5 And Brg1/smarca4 Are Independently Required For Mouse Lens Morphogenesis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5596.
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© ARVO (1962-2015); The Authors (2016-present)
ATP-dependent chromatin remodeling is an important regulatory mechanism of gene expression. Snf2h, also known as Smarca5, encodes an ATP-dependent catalytical subunit of the ISWI chromatin remodeling complexes. Our previous studies have established novel roles of Brg1/Smarca4 in lens differentiation. Herein, we performed lens-specific inactivation of Snf2h to determine its role in mammalian lens development.
We generated and analyzed lens-specific Snf2h knockout animals using the lens-specific Le-Cre mice and Snf2h flox mice. Mouse lenses from different embryonic stages and postnatal stages (E10.5 to P21) were examined using histological and immunofluorescence analysis. Post-natal day 1 (P1) wild type and Snf2h knockout eyeballs were used to prepare total RNAs for RNA expression profiling using Affymetrix microarrays. Normalized microarray data were subjected to comparative studies using GeneSpring GS8 analysis followed by gene-ontology classifications through GO and DAVID annotation tools. Snf2h microarray data was further compared with Brg1 lens conditional knockout microarray data to identify the common and distinct targets from the two models.
Lens-specific deletion of Snf2h resulted in microphthalmia, abnormal lens fiber cell differentiation and retention of nuclei in the presumptive organelle free zone. Additional abnormalities included lens-corneal stalk (Peters’ anomaly) and premature lens epithelial-to-fiber cell transition. A comparative RNA expression profiling found that Brg1 and Snf2h regulate distinct sets of genes, with only 4% of deregulated genes shared between these two systems. Down-regulation of Dnase2b and Hsf4 was found in both systems and is likely linked to the inhibition of lens fiber cell denucleation.
These studies demonstrate an essential role of Snf2h/Smarca5 in mammalian lens development and lens fiber cell denucleation. The data indicate that Brg1 (SWI/SNF) and Snf2h (ISWI) regulate mostly different batteries of target genes in lens, and perhaps in other tissues.
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