title: The Ets transcription factor EHF as a regulator of cornea epithelial cell identity.
abstract: The cornea is the clear, outermost portion of the eye composed of three layers: an epithelium that provides a protective barrier while allowing transmission of light into the eye, a collagen-rich stroma, and an endothelium monolayer. How cornea development and aging is controlled is poorly understood. Here we characterize the mouse cornea transcriptome from early embryogenesis through aging and compare it with transcriptomes of other epithelial tissues, identifying cornea-enriched genes, pathways, and transcriptional regulators. Additionally, we profiled cornea epithelium and stroma, defining genes enriched in these layers. Over 10,000 genes are differentially regulated in the mouse cornea across the time course, showing dynamic expression during development and modest expression changes in fewer genes during aging. A striking transition time point for gene expression between postnatal days 14 and 28 corresponds with completion of cornea development at the transcriptional level. Clustering classifies co-expressed, and potentially co-regulated, genes into biologically informative categories, including groups that exhibit epithelial or stromal enriched expression. Based on these findings, and through loss of function studies and ChIP-seq, we show that the Ets transcription factor EHF promotes cornea epithelial fate through complementary gene activating and repressing activities. Furthermore, we identify potential interactions between EHF, KLF4, and KLF5 in promoting cornea epithelial differentiation. These data provide insights into the mechanisms underlying epithelial development and aging, identifying EHF as a regulator of cornea epithelial identity and pointing to interactions between Ets and KLF factors in promoting epithelial fate. Furthermore, this comprehensive gene expression data set for the cornea is a powerful tool for discovery of novel cornea regulators and pathways.
authors.affiliation: From the Departments of Biological Chemistry and.
authors.forename: Denise N
authors.initials: DN
authors.lastname: Stephens
authors.forename: Rachel Herndon
authors.initials: RH
authors.lastname: Klein
authors.forename: Michael L
authors.initials: ML
authors.lastname: Salmans
authors.forename: William
authors.initials: W
authors.lastname: Gordon
authors.forename: Hsiang
authors.initials: H
authors.lastname: Ho
authors.forename: Bogi
authors.initials: B
authors.lastname: Andersen
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D003315:Cornea / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C112442:Ehf protein, mouse; C000715468:Klf4 protein, mouse; C118391:Klf5 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors
keywords: Aging; Chromatin Immunoprecipitation (ChiP); Cornea; DNA Transcription; Development; Epithelium; Eye; Gene Expression; Transcription/Developmental Factors