title: Serum response factor: positive and negative regulation of an epithelial gene expression network in the destrin mutant cornea.
abstract: Increased angiogenesis, inflammation, and proliferation are hallmarks of diseased tissues, and in vivo models of these disease phenotypes can provide insight into disease pathology. Dstn(corn1) mice, deficient for the actin depolymerizing factor destrin (DSTN), display an increase of serum response factor (SRF) that results in epithelial hyperproliferation, inflammation, and neovascularization in the cornea. Previous work demonstrated that conditional ablation of Srf from the corneal epithelium of Dstn(corn1) mice returns the cornea to a wild-type (WT) like state. This result implicated SRF as a major regulator of genes that contributes to abnormal phenotypes in Dstn(corn1) cornea. The purpose of this study is to identify gene networks that are affected by increased expression of Srf in the Dstn(corn1) cornea. Microarray analysis led to characterization of gene expression changes that occur when conditional knockout of Srf rescues mutant phenotypes in the cornea of Dstn(corn1) mice. Comparison of gene expression values from WT, Dstn(corn1) mutant, and Dstn(corn1) rescued cornea identified >400 differentially expressed genes that are downstream from SRF. Srf ablation had a significant effect on genes associated with epithelial cell-cell junctions and regulation of actin dynamics. The majority of genes affected by SRF are downregulated in the Dstn(corn1) mutant cornea, suggesting that increased SRF negatively affects transcription of SRF gene targets. ChIP-seq analysis on Dstn(corn1) mutant and WT tissue revealed that, despite being present in higher abundance, SRF binding is significantly decreased in the Dstn(corn1) mutant cornea. This study uses a unique model combining genetic and genomic approaches to identify genes that are regulated by SRF. These findings expand current understanding of the role of SRF in both normal and abnormal tissue homeostasis.
authors.affiliation: Department of Medical Genetics, University of Wisconsin, Madison, Wisconsin;
authors.forename: Sharolyn V
authors.initials: SV
authors.lastname: Kawakami-Schulz
authors.forename: Angela M
authors.initials: AM
authors.lastname: Verdoni
authors.forename: Shannon G
authors.initials: SG
authors.lastname: Sattler
authors.forename: Erik
authors.initials: E
authors.lastname: Jessen
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ikeda
authors.forename: Sakae
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003315:Cornea / Q000378:metabolism*; D051345:Destrin / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D007365:Intercellular Junctions / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D026362:Serum Response Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000199:Actins; D051345:Destrin; D026362:Serum Response Factor
keywords: SRF; cornea; destrin; epithelial gene expression