title: Cofactors of LIM Domains Associate with Estrogen Receptor α to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function.
abstract: Cofactors of LIM domain proteins, CLIM1 and CLIM2, are widely expressed transcriptional cofactors that are recruited to gene regulatory regions by DNA-binding proteins, including LIM domain transcription factors. In the cornea, epithelium-specific expression of a dominant negative (DN) CLIM under the keratin 14 (K14) promoter causes blistering, wounding, inflammation, epithelial hyperplasia, and neovascularization followed by epithelial thinning and subsequent epidermal-like differentiation of the corneal epithelium. The defects in corneal epithelial differentiation and cell fate determination suggest that CLIM may regulate corneal progenitor cells and the transition to differentiation. Consistent with this notion, the K14-DN-Clim corneal epithelium first exhibits increased proliferation followed by fewer progenitor cells with decreased proliferative potential. In vivo ChIP-sequencing experiments with corneal epithelium show that CLIM binds to and regulates numerous genes involved in cell adhesion and proliferation, including limbally enriched genes. Intriguingly, CLIM associates primarily with non-LIM homeodomain motifs in corneal epithelial cells, including that of estrogen receptor α. Among CLIM targets is the noncoding RNA H19 whose deregulation is associated with Silver-Russell and Beckwith-Wiedemann syndromes. We demonstrate here that H19 negatively regulates corneal epithelial proliferation. In addition to cell cycle regulators, H19 affects the expression of multiple cell adhesion genes. CLIM interacts with estrogen receptor α at the H19 locus, potentially explaining the higher expression of H19 in female than male corneas. Together, our results demonstrate an important role for CLIM in regulating the proliferative potential of corneal epithelial progenitors and identify CLIM downstream target H19 as a regulator of corneal epithelial proliferation and adhesion.
authors.affiliation: From the Departments of Biological Chemistry and Institute for Genomics and Bioinformatics, University of California, Irvine, California 92697 and.
authors.forename: Rachel Herndon
authors.initials: RH
authors.lastname: Klein
authors.affiliation: From the Departments of Biological Chemistry and.
authors.forename: Denise N
authors.initials: DN
authors.lastname: Stephens
authors.affiliation: Medicine and.
authors.forename: Hsiang
authors.initials: H
authors.lastname: Ho
authors.affiliation: Medicine and.
authors.forename: Jefferson K
authors.initials: JK
authors.lastname: Chen
authors.affiliation: From the Departments of Biological Chemistry and Institute for Genomics and Bioinformatics, University of California, Irvine, California 92697 and.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Salmans
authors.affiliation: From the Departments of Biological Chemistry and.
authors.forename: Winnie
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Departments of Biological Chemistry and State Key Laboratories for AgroBiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Zhengquan
authors.initials: Z
authors.lastname: Yu
authors.affiliation: From the Departments of Biological Chemistry and Institute for Genomics and Bioinformatics, University of California, Irvine, California 92697 and Medicine and bogi@uci.edu.
authors.forename: Bogi
authors.initials: B
authors.lastname: Andersen
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D019573:Epithelium, Corneal / Q000166:cytology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C094335:H19 long non-coding RNA; D060588:LIM Domain Proteins; C102084:Ldb1 protein, mouse; C106649:Ldb2 protein, mouse; D062085:RNA, Long Noncoding; D014157:Transcription Factors
keywords: cell proliferation; coregulators; corneal epithelium; epithelial cell; estrogen receptor; eye; gene regulation; noncoding RNA; stem cells